madinamerica
By Peter Simons September 4, 2018
Hallucinations and other psychotic symptoms have been reported after methylphenidate (Ritalin) treatment for ADHD, according to a new study published in the Scandinavian Journal of Child and Adolescent Psychiatry and Psychology. Erica Ramstad led the research at the Psychiatric Research Unit, Region Zealand, Slagelse, Denmark.
A previous FDA report exclusively focused on published, pharmaceutical-industry-sponsored trials of stimulants, which the authors note were at high risk of bias (including under-reporting of adverse effects). Even this report noted the prevalence of psychotic symptoms among children taking methylphenidate and the complete absence of these symptoms in the placebo group.
The current study consisted of two Cochrane systematic meta-analyses—one focused on randomized clinical trials (RCTs), and the other including observational studies and reports from non-placebo-controlled trials. Cochrane systematic meta-analyses are designed to include all available data, not just industry-supported trials, and add a method for rating the risk of bias.
The current analysis synthesized the data from 10 RCTs, 17 non-randomized studies, and 12 patient reports, for a total of 77,358 included patients. Most of the patients were in the non-randomized studies. Very few of the published studies on methylphenidate assessed for psychotic symptoms, so this research is based on those studies that did include this data.
Because the non-randomized studies only involve children taking the drug, there is no way to judge whether the drug caused the effect. Nonetheless, these studies can be used to estimate the prevalence of a symptom, and from these studies, the researchers found that approximately 1-2% of children who began taking methylphenidate then experienced psychotic symptoms as a reported adverse effect of the drug.
The RCTs, on the other hand, can be used to compare children taking the drug to children who were randomly assigned to a placebo. An analysis of these studies found that children on methylphenidate were more than twice as likely (risk ratio 2.07) to develop psychotic symptoms than children on placebo. Although this finding did not reach statistical significance, due to the small sample size in the RCTs (statistically, it could have been due to chance), it supports the idea that the children in the non-randomized studies were more likely to experience psychotic symptoms because of the drug.
The case studies provide information about how psychotic symptoms appear for children taking methylphenidate. Hallucinations (audio, visual, and tactile) were the most common psychotic symptom. The hallucinations happened between 1 hour and 1 day after the children received methylphenidate. In all 16 cases, stopping the drug also stopped the psychotic symptoms. In four cases, children were then put back on the drug—in half of those cases, the psychotic symptoms immediately came back as well. One patient, at 3-year follow-up, was still taking methylphenidate and had received an additional diagnosis of schizophrenia due to continuing psychotic symptoms.
Although stimulant medications (including methylphenidate and amphetamines) are considered first-line interventions for ADHD in children, researchers have raised numerous concerns about the effectiveness of these drugs and of the long-term dangers of children taking these drugs. In fact, long-term research has found that children who took stimulant medications either have the same results or worse results than children with ADHD who did not take stimulants.
A previous Cochrane review of the effectiveness of methylphenidate, led by some of the researchers from the current study, described the evidence of effectiveness as “very low quality” and stated that most of the studies were at “high risk of bias, imprecision, indirectness, heterogeneity and publication bias.” It appears, from these reports, that stimulants may slightly improve children’s behavior in the classroom, according to their teachers’ reports, but that any such finding should be taken with a grain of salt considering the high risk of bias in the included studies.
Because of the high risk of bias and methodological problems plaguing all the RCTs that studied methylphenidate, the authors of the current study reported that they could not say for certain that psychotic symptoms are an adverse effect of methylphenidate treatment. They suggest that future research needs to better assess for psychotic symptoms and include more rigorous, less-biased study design.
****
Ramstad, E., Storebø, O. J., Gerner, T., Krogh, H. B., Holmskov, M., Magnusson, F. L. . . . Simonsen, E. (2018). Hallucinations and other psychotic symptoms in response to methylphenidate in children and adolescents with attention-deficit/hyperactivity disorder: A Cochrane systematic review with meta-analysis and trial sequential analysis. Scandinavian Journal of Child and Adolescent Psychiatry and Psychology, 6(1). doi: 10.21307/sjcapp-2018-003 (Link)
Thank You Mr Simonds and MIA.
Showing posts with label ADHD. Show all posts
Showing posts with label ADHD. Show all posts
Tuesday, September 4, 2018
Friday, August 31, 2018
Large Increase In Poison Control Calls for Children Taking ADHD Drugs
madinamerica
Peter Simons
August 28, 2018
New data shows that calls to US poison control centers have increased significantly for children taking stimulant ADHD drugs.
New research published in the journal Pediatrics has found that calls to US poison control centers have increased significantly due to children taking ADHD stimulant medications, such as amphetamine (Adderall) and methylphenidate (Ritalin). The research was led by Gary Smith at the Center for Injury Research and Policy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio.
According to Smith, “In 2015, US poison control centers received >25800 calls involving exposures to amphetamine and methylphenidate, which are 2 medications used in the treatment of ADHD […] Stimulant medication overdoses can result in a variety of symptoms, including mydriasis, tremor, agitation, tachycardia, hyperreflexia, confusion, hallucinations, hyperthermia, and status epilepticus.”
The number of reported children inadvertently exposed to stimulant medications rose 71.2% between 2000 and 2011, before dropping slightly by 6.2% between 2011 and 2014. The researchers found that almost half (41.6%) of the exposures were due to unintentional therapeutic error, while another 39.6% were rated as accidental general exposure.
Most of the exposures for children younger than 5 were due to unintentional general exposure (for instance, they may have taken a sibling’s medication while playing), while most of the exposures for older children were due to therapeutic error (took a larger dose or more doses than prescribed, for instance). Intentional exposures were responsible for more than half (50.2%) of the calls for adolescents aged 13 to 19 years old (e.g., medication abuse and suicide attempts).
Twenty-eight percent of the calls involved documented clinical effects (such as drowsiness, irritability, tachycardia, and vomiting). In most cases, these effects were not serious, although 9.4% of the calls involved severe medical problems. The three reported deaths were all due to intentional exposures.
It is worth noting that this is an underestimate of the dangerous exposures to stimulant medications since not all exposures are reported to poison control centers.
Thank You Mr Simons and MIA.
Peter Simons
August 28, 2018
New data shows that calls to US poison control centers have increased significantly for children taking stimulant ADHD drugs.
New research published in the journal Pediatrics has found that calls to US poison control centers have increased significantly due to children taking ADHD stimulant medications, such as amphetamine (Adderall) and methylphenidate (Ritalin). The research was led by Gary Smith at the Center for Injury Research and Policy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio.
According to Smith, “In 2015, US poison control centers received >25800 calls involving exposures to amphetamine and methylphenidate, which are 2 medications used in the treatment of ADHD […] Stimulant medication overdoses can result in a variety of symptoms, including mydriasis, tremor, agitation, tachycardia, hyperreflexia, confusion, hallucinations, hyperthermia, and status epilepticus.”
The number of reported children inadvertently exposed to stimulant medications rose 71.2% between 2000 and 2011, before dropping slightly by 6.2% between 2011 and 2014. The researchers found that almost half (41.6%) of the exposures were due to unintentional therapeutic error, while another 39.6% were rated as accidental general exposure.
Most of the exposures for children younger than 5 were due to unintentional general exposure (for instance, they may have taken a sibling’s medication while playing), while most of the exposures for older children were due to therapeutic error (took a larger dose or more doses than prescribed, for instance). Intentional exposures were responsible for more than half (50.2%) of the calls for adolescents aged 13 to 19 years old (e.g., medication abuse and suicide attempts).
Twenty-eight percent of the calls involved documented clinical effects (such as drowsiness, irritability, tachycardia, and vomiting). In most cases, these effects were not serious, although 9.4% of the calls involved severe medical problems. The three reported deaths were all due to intentional exposures.
It is worth noting that this is an underestimate of the dangerous exposures to stimulant medications since not all exposures are reported to poison control centers.
“Unintentional and intentional pediatric exposures to ADHD medications are an increasing problem in the United States, affecting children of all ages,” the researchers write. “Exposures associated with suspected suicide or medication abuse and misuse among adolescents are of particular concern.”
****
King, S. A., Casavant, M. J., Spiller, H. A., Hodges, N. L.,
Chounthirath, T., & Smith, G. A. (2018). Pediatric ADHD medication
exposures reported to US poison control centers. Pediatrics, 141(6), e20173872. doi: 10.1542/peds.2017-3872 (Link)Thank You Mr Simons and MIA.
Friday, September 1, 2017
ADHD Diagnosis Based On "Illogical Rhetoric," Anaylysis Claims
madinamerica
Peter Simons August 29, 2017
In a philosophically rigorous article published in Frontiers in Psychology, Spanish researcher Marino Pérez-Álvarez examines the logic of attention-deficit hyperactivity disorder (ADHD). The two-part analysis first deconstructs the rhetoric composing the diagnosis—including the symptoms and presumed causes of the “disorder.” Pérez-Álvarez then goes on to examine the philosophical bases of the diagnosis as it exists in society.
The researcher, from the University of Oviedo, Spain, has a background in logical theory, and provides specific examples of how the ADHD diagnosis violates the requirements for logically sound argument. His main point is that the reasoning is circular. As an example: If a child exhibits the behaviors that are agreed to constitute ADHD, then the child can be said to “have” ADHD, and by circular reasoning, therefore, the ADHD “causes” those behaviors. Pérez-Álvarez calls out this type of reasoning as illogical rhetoric.
However, he also asks: even if the reasoning is flawed, is there scientific evidence that the neurodevelopmental model is accurate?
His research finds that there is not. In fact, he writes that the general assumptions of genetic research on psychological health are flawed. The assumption that genetics can “cause” behaviors is not consistent with genetic theory. He writes, “The genome mediates adaptation and response to the environment; it does not cause response and adaptive action.” That is, behaviors are not “caused” by genetics. Behaviors are responses to the environment.
Pérez-Álvarez writes that this may help explain why psychiatric researchers include such caveats in their “conclusive” ADHD literature as:
“ADHD-associated genomic variants are non-specific”
“Genomic-wide searches have yet to identify a single candidate gene”
“Specific genes or sets of genes causally linked to the disorder have yet to be discovered”
“Genome-wide associations between ADHD and individual genetic variants have yet to be found”
“The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history”
“Findings from neurobiological research do not have a direct application in daily clinical practice”
Nonetheless, the same researchers who wrote these statements advocate the neurobiological model of ADHD, stating, for example, that there is “substantial evidence for a genetic origin of ADHD”—which Pérez-Álvarez argues is an illogical way of interpreting the conclusions above. In fact, that article is even titled “Moving toward causality in attention-deficit hyperactivity disorder” which is particularly misleading since the article reviews correlational evidence, not causal conclusions.
According to Pérez-Álvarez, the current direction in ADHD research—and in psychiatric research in general—is to use larger and larger samples in order to find smaller and smaller correlations. But he remarks that a tiny correlation that only shows up when you sample hundreds of thousands of people is not of any value to individual diagnosis.
He writes that researchers in psychiatry often work around the lack of evidence for their standpoint by arguing that “ADHD is a ‘heterogeneous,’ ‘multifactorial,’ or ‘complex’ disorder”—which may be true, but does not excuse researchers from the burden of showing data that can back up their claims.
Pérez-Álvarez also takes aim at the rhetoric of referring to brain-based findings as “bases” and “causes” rather than simple correlates. After all, “As studies show, the brains of taxi drivers and musicians show alterations in specific areas and connections associated with their activities compared to those who are not…” but those neural correlates are certainly not presumed to be the cause of driving taxis or playing the violin. Quite the opposite, in fact—those brain changes are understood to be results of those professions. So why do researchers assume that any brain differences detected when studying people that have been diagnosed are “causing” ADHD?
A key point made by Pérez-Álvarez is that although psychiatric diagnoses may be reliable—psychiatrists may agree on the criteria—there is no evidence that they are valid. Pérez-Álvarez quotes Thomas Insel (then Director of the National Institute of Mental Health) to make this point:
“The strength of each of the editions of DSM has been ‘reliability’—each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.”
To further clarify the difference between reliability and validity, Pérez-Álvarez cites A. Marcia Angell, ex-director of the New England Journal of Medicine, who writes:
“If nearly all physicians agreed that freckles were a sign of cancer, the diagnosis would be ‘reliable,’ but not valid. The problem with the DSM is that in all of its editions, it has simply reflected the opinions of its writers.”
It is important to note that Pérez-Álvarez also argues that ADHD is “real” inasmuch as “the diagnosis already functions as a “cultural idiom.” The construct of ADHD serves to explain a way of being in relation to others that is culturally unacceptable—namely, being more active, more distractible, and more impulsive than other children.
He writes that the diagnosis of ADHD fits perfectly in a long tradition of psychiatry selecting ways of being that are considered culturally invalid, selecting and exaggerating behaviors as “symptoms,” and creating a category or label that can serve as a self-reinforcing a priori concept.
According to Pérez-Álvarez, “Any problems related to “attention,” “activity,” and “impulsivity” are not outside learning as aspects of the development of self-control. Some children may require additional “training” (not treatment).” That is, diagnosing these traits as a “brain disorder” and medicating children only serves to prevent children from learning skills of self-regulation and maintaining attention. Pérez-Álvarez advocates methods of teaching children these skills as part of the developmental process, rather than pathologizing children for acting impulsively and inattentively.
Pérez-Álvarez writes, “Attention-Deficit/Hyperactivity Disorder harmonizes a variety of scientific, medical, educational and family interests besides pharmaceutical industry profits (the most openly shameless and rightly denounced). The only party harmed seems to be the children.”
****
Pérez-Álvarez, M. (2017). The four causes of ADHD: Aristotle in the classroom. Front. Psychol. 8(928). doi: 10.3389/fpsyg.2017.00928 (Link)
Previous articleGreed Disguised as Science: How a Multitude of Factors Led to the Opioid Crisis
Next articleThe Disturbing Link Between Frequent Nightmares and Suicide
https://psychroaches.blogspot.com/search/label/Nightmare
Peter Simons
MIA-UMB News Team: Peter Simons comes from a background in the humanities where he studied English, philosophy, and art. Now working on his PhD in Counseling Psychology, his recent research has focused on conflicts of interest in the psychopharmaceutical research literature, the use of antipsychotic medications in the treatment of depression, and the general philosophical and sociopolitical implications of psychiatric taxonomy in diagnosis and treatment.
Thank You Mr Simons and MIA.
Peter Simons August 29, 2017
In a philosophically rigorous article published in Frontiers in Psychology, Spanish researcher Marino Pérez-Álvarez examines the logic of attention-deficit hyperactivity disorder (ADHD). The two-part analysis first deconstructs the rhetoric composing the diagnosis—including the symptoms and presumed causes of the “disorder.” Pérez-Álvarez then goes on to examine the philosophical bases of the diagnosis as it exists in society.
The researcher, from the University of Oviedo, Spain, has a background in logical theory, and provides specific examples of how the ADHD diagnosis violates the requirements for logically sound argument. His main point is that the reasoning is circular. As an example: If a child exhibits the behaviors that are agreed to constitute ADHD, then the child can be said to “have” ADHD, and by circular reasoning, therefore, the ADHD “causes” those behaviors. Pérez-Álvarez calls out this type of reasoning as illogical rhetoric.
However, he also asks: even if the reasoning is flawed, is there scientific evidence that the neurodevelopmental model is accurate?
His research finds that there is not. In fact, he writes that the general assumptions of genetic research on psychological health are flawed. The assumption that genetics can “cause” behaviors is not consistent with genetic theory. He writes, “The genome mediates adaptation and response to the environment; it does not cause response and adaptive action.” That is, behaviors are not “caused” by genetics. Behaviors are responses to the environment.
Pérez-Álvarez writes that this may help explain why psychiatric researchers include such caveats in their “conclusive” ADHD literature as:
“ADHD-associated genomic variants are non-specific”
“Genomic-wide searches have yet to identify a single candidate gene”
“Specific genes or sets of genes causally linked to the disorder have yet to be discovered”
“Genome-wide associations between ADHD and individual genetic variants have yet to be found”
“The genetic risks implicated in ADHD generally tend to have small effect sizes or be rare and often increase risk of many other types of psychopathology. Thus, they cannot be used for prediction, genetic testing or diagnostic purposes beyond what is predicted by a family history”
“Findings from neurobiological research do not have a direct application in daily clinical practice”
Nonetheless, the same researchers who wrote these statements advocate the neurobiological model of ADHD, stating, for example, that there is “substantial evidence for a genetic origin of ADHD”—which Pérez-Álvarez argues is an illogical way of interpreting the conclusions above. In fact, that article is even titled “Moving toward causality in attention-deficit hyperactivity disorder” which is particularly misleading since the article reviews correlational evidence, not causal conclusions.
According to Pérez-Álvarez, the current direction in ADHD research—and in psychiatric research in general—is to use larger and larger samples in order to find smaller and smaller correlations. But he remarks that a tiny correlation that only shows up when you sample hundreds of thousands of people is not of any value to individual diagnosis.
He writes that researchers in psychiatry often work around the lack of evidence for their standpoint by arguing that “ADHD is a ‘heterogeneous,’ ‘multifactorial,’ or ‘complex’ disorder”—which may be true, but does not excuse researchers from the burden of showing data that can back up their claims.
Pérez-Álvarez also takes aim at the rhetoric of referring to brain-based findings as “bases” and “causes” rather than simple correlates. After all, “As studies show, the brains of taxi drivers and musicians show alterations in specific areas and connections associated with their activities compared to those who are not…” but those neural correlates are certainly not presumed to be the cause of driving taxis or playing the violin. Quite the opposite, in fact—those brain changes are understood to be results of those professions. So why do researchers assume that any brain differences detected when studying people that have been diagnosed are “causing” ADHD?
A key point made by Pérez-Álvarez is that although psychiatric diagnoses may be reliable—psychiatrists may agree on the criteria—there is no evidence that they are valid. Pérez-Álvarez quotes Thomas Insel (then Director of the National Institute of Mental Health) to make this point:
“The strength of each of the editions of DSM has been ‘reliability’—each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure.”
To further clarify the difference between reliability and validity, Pérez-Álvarez cites A. Marcia Angell, ex-director of the New England Journal of Medicine, who writes:
“If nearly all physicians agreed that freckles were a sign of cancer, the diagnosis would be ‘reliable,’ but not valid. The problem with the DSM is that in all of its editions, it has simply reflected the opinions of its writers.”
It is important to note that Pérez-Álvarez also argues that ADHD is “real” inasmuch as “the diagnosis already functions as a “cultural idiom.” The construct of ADHD serves to explain a way of being in relation to others that is culturally unacceptable—namely, being more active, more distractible, and more impulsive than other children.
He writes that the diagnosis of ADHD fits perfectly in a long tradition of psychiatry selecting ways of being that are considered culturally invalid, selecting and exaggerating behaviors as “symptoms,” and creating a category or label that can serve as a self-reinforcing a priori concept.
According to Pérez-Álvarez, “Any problems related to “attention,” “activity,” and “impulsivity” are not outside learning as aspects of the development of self-control. Some children may require additional “training” (not treatment).” That is, diagnosing these traits as a “brain disorder” and medicating children only serves to prevent children from learning skills of self-regulation and maintaining attention. Pérez-Álvarez advocates methods of teaching children these skills as part of the developmental process, rather than pathologizing children for acting impulsively and inattentively.
Pérez-Álvarez writes, “Attention-Deficit/Hyperactivity Disorder harmonizes a variety of scientific, medical, educational and family interests besides pharmaceutical industry profits (the most openly shameless and rightly denounced). The only party harmed seems to be the children.”
****
Pérez-Álvarez, M. (2017). The four causes of ADHD: Aristotle in the classroom. Front. Psychol. 8(928). doi: 10.3389/fpsyg.2017.00928 (Link)
Previous articleGreed Disguised as Science: How a Multitude of Factors Led to the Opioid Crisis
Next articleThe Disturbing Link Between Frequent Nightmares and Suicide
https://psychroaches.blogspot.com/search/label/Nightmare
Peter Simons
MIA-UMB News Team: Peter Simons comes from a background in the humanities where he studied English, philosophy, and art. Now working on his PhD in Counseling Psychology, his recent research has focused on conflicts of interest in the psychopharmaceutical research literature, the use of antipsychotic medications in the treatment of depression, and the general philosophical and sociopolitical implications of psychiatric taxonomy in diagnosis and treatment.
Thank You Mr Simons and MIA.
Thursday, April 6, 2017
Withdrawal From ADHD Medications
madinamerica
By Shannon Peters December 19, 2016
Editor’s note: We know that our reviews of the withdrawal literature are incomplete, and we urge readers to help us add to these withdrawal reviews. Please send study citations that are relevant to the withdrawal literature for stimulants to rwhitaker@madinamerica.com.
Introduction
Much of the research on withdrawal from stimulant drugs is focused on the effects of withdrawal from recreational use or abuse of these drugs, as opposed to modeling discontinuation of these drugs following treatment for ADHD. This is true of both the animal studies and human studies. Nevertheless, this research literature provides insight into how stimulant use changes the brain; possible long-lasting behavioral effects from such brain changes, and withdrawal symptoms.
Mechanism of Action and Drug-Induced Compensatory Response
Both stimulants and non-stimulants are prescribed to treat ADHD. Stimulant medications are the most commonly prescribed, and are of two classes: amphetamines and methylphenidate. The amphetamines include mixed amphetamine salts (Adderall), dextroamphetamine (Dexedrine), and lisdexamfetamine (Vyanse). Amphetamines increase the amount of norepinephrine, serotonin, and dopamine in the brain by increasing the neuronal release of these neurotransmitters into the synaptic cleft (the tiny gap between neurons.)
The methylphenidate stimulants include Ritalin, Concerta, and Daytrana, and also dexmethylphenidate (Focalin). Methlyphenidates increase dopamine and norepinephrine activity in the brain by blocking their reuptake from the synaptic cleft. The neurotransmitters thus remain longer than normal in the synaptic cleft.
There are also two classes of non-stimulants for ADHD. Atomoxetine (Strattera) inhibits the reuptake of norepinephrine, and thus increases norepinephrine activity in the brain. The second class of non-stimulants are alpha adrenergic agents, such as guanfacine (Intuniv) and clonidine (Kapvay). Alpha adrenergic agents mimic epinephrine and norepinephrine and stimulate the same receptors as these neurotransmitters.
Given that these drugs increase dopamine and norepinephrine activity, they trigger compensatory responses in the brain that, in one way or another, alter this activity. These compensatory changes may include a change in the density of dopamine and norepinephrine receptors; a decrease in the production and release of these molecules by the presynaptic neurons; and changes in the density of transporter molecules involved in the reuptake of the neurotransmitters from the synaptic cleft.
Animal Studies
There is an abundance of animal research on the effects of withdrawal from stimulant drugs, mainly in the form of rat studies. Many of these studies focus on the effect of medications during adolescence on later drug abuse, with contradictory findings. However, in general, the animal studies on stimulant drug withdrawal strongly suggest that the drug exposure leads to a number of both short-term and long-lasting behavioral effects and brain changes.
Models of brain changes follow withdrawal from ADHD medications
Barr JL, Renner KJ, Forster GL. Withdrawal from chronic amphetamine produces persistent anxiety-like behavior but temporally-limited reductions in monoamines and neurogenesis in the adult rat dentate gyrus. Neuropharmacology. 2010;59(6):395-405. PubMed Link
In this study, researchers exposed adult male rats to amphetamine for two weeks and monitored them for four weeks of withdrawal. Results showed that rats had increased anxiety behaviors during withdrawal. The rats’ corticosterone levels were unchanged. Their norepinephrine and serotonin levels in the dentate gyrus of the brain were reduced immediately following treatment, showing evidence of reduced neurogenesis, or new neuron growth, but the levels did not remain low by the end of the study.
2) Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One. 2012;7(3):e33693. PubMed Link
Researchers administered methylphenidate at two doses to rats for 90 days during the developmental period that matches adolescence and young adulthood in humans, and studied the effects on the brain seven days after withdrawal. Researchers found increased levels of dopamine in the striatum for the lower dose, but not higher dose, of methylphenidate. The authors concluded that long-term therapeutic doses of methylphenidate can have long-term degenerating effects in the brain.
3) Somkuwar SS, Kantak KM, Dwoskin LP. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder. Journal of Neuroscience Methods. 2015;252:55-63. PubMed Link
Researchers orally exposed rats to methylphenidate from early to late adolescence and then discontinued the drug. Researchers found that during treatment, rats exposed to methylphenidate had lower than normal rates of norepinephrine reuptake. and considered this a normalization of the norepinephrine transporter through treatment. Three to five weeks after discontinuation, norepinephrine transporter function remained at this lower rate which the researchers concluded as persisting treatment effects even after drug discontinuation.
Impacts of ADHD medication treatment and withdrawal on later drug use
4) Brandon CL, Marinelli M, Baker LK, White FJ. Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology. 2001;25(5):651-61. PubMed Link
Researchers exposed rats to methylphenidate during adolescence, withdrew the drug, and then studied rats’ behavior toward cocaine as adults. Findings showed that rats exposed to low doses, but not moderate doses, of methylphenidate engaged in more cocaine self-administration. Researchers concluded that early exposure to low doses of methylphenidate may increase susceptibility to low doses of cocaine, and consequently increase risk of cocaine use as adults.
5) Andersen SL, Arvanitogiannis A, Pliakas AM, LeBlanc C, Carlezon WA. Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nature Neuroscience. 2002;5(1):13-4. PubMed Link
Researchers exposed pre-adolescent rats to methylphenidate and then withdrew the drug in order to study its effects on the rats’ responsiveness to cocaine in adulthood. They found that the rats were less responsive to cocaine’s rewarding effects and concluded that pre-adolescent exposure to methylphenidate may cause lasting changes to dopaminergic function. The researchers also studied rats exposed to methylphenidate in adulthood and concluded that neurobiological effects differ depending on the developmental stage when rats are exposed to the medication.
6) Carlezon WA, Mague SD, Andersen SL. Enduring behavioral effects of early exposure to methylphenidate in rats. Biological Psychiatry. 2003;54(12):1330-7. PubMed Link
In this study, researchers examined how exposure to methylphenidate or cocaine in preadolescence affected behaviors in adult rats. Researchers found that exposure to methylphenidate in preadolescence can cause behavioral changes in adulthood including finding cocaine less rewarding and demonstrating depressive-like symptoms.
7) Mague SD, Andersen SL, Carlezon WA. Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats. Biological Psychiatry. 2005;57(2):120-5. PubMed Link
Researchers exposed rats to methylphenidate during pre-adolescence, withdrew the drug, and then studied the impacts on cocaine’s ability to simulate the reward system in the brain. The authors found that early exposure to methylphenidate resulted in a decreased effect of cocaine on the reward system, suggesting that the dopamine system functioned in an abnormal manner.
8) Augustyniak PN, Kourrich S, Rezazadeh SM, Stewart J, Arvanitogiannis A. Differential behavioral and neurochemical effects of cocaine after early exposure to methylphenidate in an animal model of attention deficit hyperactivity disorder. Behavioural Brain Research. 2006;167(2):379-82. PubMed Link
Researchers exposed pubertal rats to methylphenidate and then withdrew the drug to examine its effects on cocaine use and dopamine levels in adulthood. The researchers found that the exposure reduced the rats’ sensitivity to cocaine in adulthood, but did not alter the dopamine system in the mesolimbic brain pathway.
9) Gill KE, Pierre PJ, Daunais J, Bennett AJ, Martelle S, Gage HD, Swanson JM, Nader MA, Porrino LJ. Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates. Neuropsychopharmacology. 2012;37(12):2555-65. PubMed Link
In this rhesus monkey model for ADHD treatment, monkeys were given methylphenidate for a year and studied 3-5 months after discontinuation of treatment. Findings showed that methylphenidate-treated monkeys had unchanged levels of specific dopamine receptor, D2/D3, while controls had a decreasing number of receptors (a decrease of receptors in this context is seen as a developmental process of synaptic pruning). The authors found no evidence that methylphenidate increases vulnerability to cocaine later in life.
10) Somkuwar SS, Jordan CJ, Kantak KM, Dwoskin LP. Adolescent atomoxetine treatment in a rodent model of ADHD: effects on cocaine self-administration and dopamine transporters in frontostriatal regions. Neuropsychopharmacology. 2013;38(13):2588-97. PubMed Link
Researchers exposed rats to atomoxetine during adolescence, withdrew the drug, and then studied the impacts on cocaine self-administration and on dopamine and norepinephrine transporters. Findings showed that atomoxetine did not increase vulnerability to cocaine and authors concluded that atomoxetine may be a better treatment choice than methylphenidate when the prescriber is worried about drug abuse.
11) Jordan CJ, Harvey RC, Baskin BB, Dwoskin LP, Kantak KM. Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments. Drug and Alcohol Dependence. 2014;140:25-32. PubMed Link
Researchers exposed rats to methylphenidate and atomoxetine during adolescence, withdrew the drug, and then studied rats’ cocaine-seeking behavior as adults. Results showed that adult rats previously treated with methylphenidate had increased cocaine intake, but there was no increase in cocaine intake for rats previously treated with atomoxetine. Neither drug resulted in increases in cocaine seeking in adulthood.
12) Jordan CJ, Taylor DM, Dwoskin LP, Kantak KM. Adolescent D-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood. Behavioural Brain Research. 2016;297:165-79. PubMed Link
Researchers exposed rats to d-amphetamine during adolescence, withdrew the drug, and then studied rats’ cocaine-seeking behavior as adults. The findings showed that d-amphetamine exposure during adolescence did not change self-administration of cocaine and decreased cocaine-seeking behavior in adulthood. The authors concluded that treatment with d-amphetamine may result in lower risk of future cocaine use than methylphenidate treatment.
Behavioral impacts of withdrawal
13) Herman ZS, Trzeciak H, Chruściel TL, Kmieciak-Kołada K, Drybański A, Sokoła A. The influence of prolonged amphetamine treatment and amphetamine withdrawal on brain biogenic amine content and behaviour in the rat. Psychopharmacologia. 1971;21(1):74-81. PubMed Link
Researchers exposed rats to D–L-amphetamine sulphate for 9 months and studied the behavioral effects of the drug and drug withdrawal. Authors found that, during withdrawal, rats moved around less (measured for 12 days post-withdrawal) and had lower levels of noradrenaline and serotonin in the cerebellum part of the brain (measured at 3 days post-withdrawal).
14) Leith NJ, Barrett RJ. Amphetamine and the reward system: evidence for tolerance and post-drug depression. Psychopharmacologia. 1976;46(1):19-25. PubMed Link
In this study, researchers measured the effects of withdrawal from d-amphetamine on self-electrical brain stimulation, examining effects on the reward system in the brain. One day after d-amphetamine withdrawal, rats had reduced self-stimulation, which the authors interpreted as dysregulation in the brain’s reward system and depression.
15) Schreiber H, Bell R, Conely L, Kufner M, Palet J, Wright L. Diminished reaction to a novel stimulus during amphetamine withdrawal in rats. Pharmacology Biochemistry and Behavior. 1976;5(6):687-90. PubMed Link
Researchers examined the effects of d-amphetamine withdrawal on response to a new stimulus. Rats were exposed to two doses of d-amphetamine or saline for eight days and tested one day after discontinuing the drug. Findings showed that rats exposed to more d-amphetamine had the least response to a new stimulus and rats exposed to the smaller dose of d-amphetamine had less response than control rats.
16) Simpson DM, Annau Z. Behavioral withdrawal following several psychoactive drugs. Pharmacology Biochemistry and Behavior. 1977;7(1):59-64. PubMed Link
In this rat study, researchers assessed behavioral withdrawal from four types of psychoactive drugs, including amphetamine, by measuring self-electrical stimulation of the brain. Findings showed that rats exposed to amphetamine had increased rates of self-stimulation while on the drug, but decreased their self-stimulation during withdrawal.
17) Cassens G, Actor C, Kling M, Schildkraut JJ. Amphetamine withdrawal: Effects on threshold of intracranial reinforcement. Psychopharmacology. 1981;73(4):318-22. PubMed Link
In this rat study, researchers examined the effects of withdrawal from d-amphetamine on the threshold to activate the reward system in the brain. Results showed an increased threshold, meaning rats found a stimulus less rewarding than control rats, within 24 hours of withdrawal, with the highest threshold increase around 24 to 72 hours.
18) Kokkinidis L, Zacharko RM, Anisman H. Amphetamine withdrawal: A behavioral evaluation. Life sciences. 1986;38(17):1617-23. PubMed Link
In this study, researchers exposed mice to amphetamines for 10 days and studied the behavioral effects of withdrawal 24 hours after the mice’s last exposure to amphetamine. Results showed that withdrawn mice responded less to electrical stimulation in the brain, and moved less in the forced swim test. However, withdrawn mice did not differ from controls on behaviors in the shuttle escape task or acoustic startle reflex. The authors concluded that depressive behaviors induced by amphetamine withdrawal are due more to motivation than mechanisms of motor-activity or arousal.
19) Paulson PE, Camp DM, Robinson TE. Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacology. 1991;103(4):480-92. PubMed Link
In this rat study, researchers investigated the withdrawal syndrome for d-amphetamine. Researchers found that withdrawn rats showed depressive behaviors as soon as two days post-withdrawal, but the behaviors were gone by one month. Depressive behaviors were associated with short-term lower levels of norepinephrine in the hypothalamus part of the brain.
20) Schindler CW, Persico AM, Uhl GR, Goldberg SR. Behavioral assessment of high-dose amphetamine withdrawal: importance of training and testing conditions. Pharmacology Biochemistry and Behavior. 1994;49(1):41-6. PubMed Link
In this rat study, researchers investigated the effects of withdrawal from chronic (2 weeks) versus acute (one time) d-amphetamine use. Results showed that chronic rats engaged in less movement in a locomotor activity test 24-54 hours after withdrawal, and engaged in less movement during a swim test 36-72 hours after withdrawal.
21) Wise RA, Munn E. Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology. 1995;117(2):130-6. PubMed Link
In this rat study, researchers measured self-stimulation of the lateral hypothalamus in the brain after withdrawal from amphetamine. Rats were exposed to amphetamine for six weeks and self-stimulation was measured starting at 36 hours post-withdrawal up to three weeks. Authors found that drug withdrawn rats engaged in self-stimulation less frequently and had higher thresholds, meaning they required a stronger stimulus to engage in self-stimulation. By two weeks after drug discontinuation, amphetamine exposed rats did not differ from control rats.
22) Barr AM, Phillips AG. Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement. Psychopharmacology. 1999;141(1):99-106. PubMed Link
In this rat study, researchers investigated whether withdrawal from d-amphetamine after four days of exposure reduced rats’ effort for a natural reward of sugar water. Results showed that rats withdrawing from the drug were less motivated to obtain a natural reward.
23) Barr AM, Fiorino DF, Phillips AG. Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat. Pharmacology Biochemistry and Behavior. 1999;64(3):597-604. PubMed Link
In this rat study, researchers investigated the impact of withdrawal from d-amphetamine on sexual behavior in male rats. Rats were exposed to d-amphetamine for four days and tested 12 hours after final dose. The results showed decreased motivation in preparatory sexual behaviors, but no change in consummatory behaviors.
24) Barr AM, Phillips AG. Increased successive negative contrast in rats withdrawn from an escalating-dose schedule of D-amphetamine. Pharmacology Biochemistry and Behavior. 2002;71(1):293-9. PubMed Link
In this rat study, researchers examined the effects of withdrawal from d-amphetamine on behavior by measuring their consumption of sugar water compared to rats not exposed to the drug. Findings showed rats withdrawn from d-amphetamine that were previously given 34% sugar water and then given 4% sugar water consumed much less than controls for up to 60 hours. The authors understood this behavior to be connected to higher emotionality during withdrawal.
25) Russig H, Durrer A, Yee BK, Murphy CA, Feldon J. The acquisition, retention and reversal of spatial learning in the Morris water maze task following withdrawal from an escalating dosage schedule of amphetamine in Wistar rats. Neuroscience. 2003;119(1):167-79. PubMed Link
In this rat study, researchers examined the effects of d-amphetamine withdrawal on spatial learning using the Morris water maze task. Researchers found that rats withdrawing from amphetamine had enhanced reversal learning (learning to locate a new place in the water maze) than control rats.
26) Cryan JF, Hoyer D, Markou A. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biological Psychiatry. 2003;54(1):49-58. PubMed Link
In this rat study, researchers investigated behavioral effects of amphetamine withdrawal. Findings showed a number of changes in behavior that reflect depressive symptoms including higher thresholds to activate reward system, less swimming and climbing behaviors in a forced swim test, and less movement in a mouse tail suspension test, lasting for the 72 hours of observation.
27) Peterson JD, Wolf ME, White FJ. Impaired DRL 30 performance during amphetamine withdrawal. Behavioural Brain Research. 2003;143(1):101-8. PubMed Link
In this rat study, researchers measured impulsivity during amphetamine withdrawal by measuring rats’ ability to wait at least 30 seconds to poke a hole with their nose in order to receive food. Rats were exposed to amphetamine for five days and then withdrawn from amphetamine for three days before testing began. Researchers found amphetamine withdrawn rats had more nose pokes than controls, demonstrating higher rates of impulsivity, for up to two weeks after withdrawal.
28) Che Y, Cui YH, Tan H, Andreazza AC, Young LT, Wang JF. Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain. Psychopharmacology. 2013;227(4):605-14. PubMed Link
In this rat study, researchers explored causes of depressive symptoms in amphetamine withdrawal. Results showed that rats demonstrated depressive symptoms during withdrawal and that withdrawal caused oxidative damage in the brain.
Physiological Impacts of Withdrawal
29) Lynch MA, Leonard BE. Changes in brain γ-aminobutyric acid concentrations following acute and chronic amphetamine administration and during post amphetamine depression. Biochemical pharmacology. 1978;27(14):1853-5. PubMed Link
In this rat study, researchers investigated changes of GABA, an inhibitory neurotransmitter, in different parts of the brain from d-amphetamine exposure and withdrawal. After an increase in GABA during administration of the drug, researchers found that GABA levels decreased to normal levels compared to the control group within 7 days of withdrawal in the striatum and brain stem. They also found that GABA levels in the amygdala increased during withdrawal. The authors described the rats as behaviorally depressed during withdrawal.
30) Cassens G, Kuruc A, Orsulak PJ, Schildkraut JJ. Amphetamine withdrawal: effects on brain levels of MHPG-SO4 in the rat. Communications in psychopharmacology. 1979;3(4):217. PubMed Link
In this rat study, researchers measured brain levels of a metabolite of norepinephrine, MHPG-SO4, after withdrawal from d-amphetamine. The authors found that up to 48 hours after withdrawal, rats had decreased MHPG-SO4 levels.
31) Koike Y, Togashi H, Shimamura K, Yomaida I, Saito H. Effects of abrupt cessation of treatment with clonidine and guanfacine on blood pressure and heart rate in spontaneously hypertensive rats. Clinical and experimental hypertension. 1981;3(1):103-20. PubMed Link
In this rat study, authors researched the impact of guanfacine withdrawal on blood pressure. Rats had low blood pressure while exposed to 5 weeks of guanfacine, and abrupt discontinuation of the medication did not result in a fast rise in blood pressure.
32) Ricaurte G, Seiden LS, Schuster C. Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers. Brain Research. 1984;303(2):359-64. PubMed Link
In this rat study, researchers administered either methamphetamine or amphetamine to rats for three days and then studied the effects on the brain two weeks after withdrawal. The authors found decreased levels of dopamine and evidence of nerve fiber degeneration in the striatum.
33) Swerdlow NR, Hauger R, Irwin M, Koob GF, Britton KT, Pulvirenti L. Endocrine, immune, and neurochemical changes in rats during withdrawal from chronic amphetamine intoxication. Neuropsychopharmacology. 1991;5(1):23-31. PubMed Link
In this rat study, researchers examined the impacts of withdrawal from 10-day amphetamine exposure. The researchers found that adrenocorticotropic hormone and corticosterone levels, which are normally correlated, uncoupled by the fifth day of withdrawal, with the effect persisting for the 10 days of observation. They also found decreased levels of dopamine and its metabolite, DOPAC, in certain brain regions. The researchers concluded this represented dysregulation in the hypothalamic–pituitary–adrenal axis.
34) Rossetti ZL, Hmaidan Y, Gessa GL. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. European Journal of Pharmacology. 1992;221(2-3):227-34. PubMed Link
In this rat study, authors investigated the effects on dopamine levels in the brain for a number of drugs that are frequently abused. The authors found that with amphetamine withdrawal, dopamine levels decreased quickly, to about 50% of control levels in the first day, and remained low for several days, and then return to levels equivalent to controls within 10 days.
35) Persico AM, Schindler CW, Brannock MT, Gonzalez AM, Surratt CK, Uhl GR. Dopaminergic gene expression during amphetamine withdrawal. Neuroreport. 1993;4(1):41-4. PubMed Link
In this rat study, researchers studied the effects of amphetamine withdrawal on gene expression that affects dopamine. The researchers did not find changes in dopaminergic gene expression, but found a slight increase in tyrosine hydroxylase gene expression and substantially decreased expression of a specific amine transporter, both of which are involved in dopamine transmission. The authors concluded that these changes in gene expression may be involved in restoring the balance of dopamine in the brain.
36) Persico AM, Schindler CW, Zaczek R, Brannock MT, Uhl GR. Brain transcription factor gene expression, neurotransmitter levels, and novelty response behaviors: alterations during rat amphetamine withdrawal and following chronic injection stress. Synapse. 1995;19(3):212-27. PubMed Link
In this rat study, researchers explored the effects of withdrawal from amphetamine on transcription factors that impact neurotransmitter gene expression in the brain. Findings showed decreased transcription factor and decreased dopamine levels in areas of the brain within 12 hours of withdrawal. The levels returned to normal, compared to control, by 54 hours.
37) Paulson PE, Robinson TE. Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum: analysis of circadian patterns using automated on-line microdialysis. Neuropsychopharmacology. 1996;14(5):325. PubMed Link
In this rat study, researchers explored behavioral symptoms and their connection to dopamine concentration in different brain regions during circadian rhythms at 3, 7, and 28 days post amphetamine withdrawal. Rats displayed depressive behaviors within a week of drug discontinuation and at 3 and 7 days post-withdrawal, rats had decreases in dopamine in the dorsolateral caudate nucleus. At 28 days, rats no longer presented with depressive behaviors and dopamine levels increased in the caudate and accumbens parts of the brain.
38) Melega WP, Raleigh MJ, Stout DB, Huang SC, Phelps ME. Ethological and 6-[18F] fluoro-L-DOPA-PET profiles of long-term vulnerability to chronic amphetamine. Behavioural Brain Research. 1997;84(1):259-68. PubMed Link
In this study on vervet monkeys, researchers used PET scans to measure dopamine function in the striatum of the brain. The researchers administered amphetamine to the monkeys to increase dopamine function, and then withdrew the drug after ten days. Findings showed that monkeys slowly recovered baseline dopamine functioning after 24 months of drug discontinuation.
39) Robinson TE, Kolb B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. The Journal of Neuroscience. 1997;17(21):8491-7. PubMed Link
In this rat study, researchers examined the changes in the brain caused by exposure to amphetamine for a month after discontinuing the drug. They found a number of structural changes to neurons in specific parts of the brain that affect communication between neurons and hypothesized that these changes are connected to behavioral changes seen in humans after withdrawal from amphetamine abuse.
40) Raheem KA, Ismael N, Saad A, El-Sayad S. Gluconeogenic activity in response to chronic administration of amphetamine sulphate and drug withdrawal. General Pharmacology: The Vascular System. 1997;29(4):687-90. PubMed Link
In this rat study, researchers explored the impact of chronic amphetamine use and withdrawal on serum levels. Results showed that rats that discontinued amphetamine after four weeks of use had glucose levels close to controls, and glutamate oxaloacetic transaminase (GOT) enzyme activity returned to normal, but corticosterone levels remained elevated during 30 hours of studied withdrawal. The authors conclude rats can recover from the effects of amphetamine after withdrawing from the drug.
41) Lu W, Monteggia LM, Wolf ME. Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex. European Journal of Neuroscience. 1999;11(9):3167-77. PubMed Link
In this rat study, researchers investigated whether NMDA receptors, a neuron receptor for the neurotransmitter glutamate, were altered by amphetamine use even after withdrawal. The researchers did not find changes in a subunit of the NMDA receptor after three days of withdrawal, but found decreased expression of the subunit of the receptor 14 days after withdrawal. The authors hypothesized that this may signify reduced excitation in dopaminergic neurons.
42) Onn SP, Grace AA. Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. The Journal of Neuroscience. 2000;20(6):2332-45. PubMed Link
In this rat study, researchers explored changes in gap junction functioning, a type of communication between neurons, in the corticoaccumbens network after withdrawal from amphetamine. Researchers found changes in gap junction function 28 days after withdrawal.
43) Murphy CA, Russig H, Pezze MA, Ferger B, Feldon J. Amphetamine withdrawal modulates FosB expression in mesolimbic dopaminergic target nuclei: effects of different schedules of administration. Neuropharmacology. 2003;44(7):926-39. PubMed Link
In this rat study, researchers investigated the effects on gene expression of withdrawal from a low dose compared to a moderately high dose of amphetamine. Findings showed an increased expression of the FosB gene only in the higher dose. The authors concluded that withdrawal from a higher dose of amphetamine changes gene expression that impacts dopamine, but that does not affect monoamine levels.
44) Kolb B, Gorny G, Li Y, Samaha AN, Robinson TE. Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens. Proceedings of the National Academy of Sciences. 2003;100(18):10523-8. PubMed Link
In this rat study, researchers examined the effects of amphetamine and cocaine use on neural plasticity, the ability for the brain to adapt, after 3.5 months of withdrawal. The authors found that rats previously exposed to amphetamine had inhibited neural plasticity when exposed to a complex environment and concluded that even after withdrawal, amphetamine use may lead to persistent behavioral and cognitive deficits.
45) Mohila CA, Onn SP. Increases in the density of parvalbumin-immunoreactive neurons in anterior cingulate cortex of amphetamine-withdrawn rats: evidence for corticotropin-releasing factor in sustained elevation. Cerebral Cortex. 2005;15(3):262-74. PubMed Link
In this rat study, researchers investigated changes to the inhibitory neurotransmitter, GABA’s, signaling in the brain during withdrawal from amphetamines. Researchers concluded that withdrawal from amphetamine alters GABA signaling.
46) McCracken CB, Patel KM, Vrana KE, Paul DL, Roberts D. Amphetamine withdrawal produces region‐specific and time‐dependent changes in connexin36 expression in rat brain. Synapse. 2005;56(1):39-44. PubMed Link
In this rat study, researchers explored changes in gap junction functioning, a type of communication between neurons, after withdrawal from extended amphetamine exposure. Findings showed that during the withdrawal period there were changes in the expression of a gap junction protein, connexin36, in brain regions considered to be involved in sensitization and addiction.
47) Russig H, Pryce CR, Feldon J. Amphetamine withdrawal leads to behavioral sensitization and reduced HPA axis response following amphetamine challenge. Brain Research. 2006;1084(1):185-95. PubMed Link
In this rat study, researchers investigated stress hormone release related to depression-like symptoms during amphetamine withdrawal. Rats were exposed to amphetamine three times a day for three days and withdrawal was studied for 30 days. Results showed no effect of withdrawal on release of adrenocorticotropic hormone or corticosterone in stressful situations.
48) Parelkar NK, Wang JQ. Upregulation of metabotropic glutamate receptor 8 mRNA expression in the rat forebrain after repeated amphetamine administration. Neuroscience Letters. 2008;433(3):250-4. PubMed Link
In this rat study, researchers measured gene expression of glutamate receptors in the forebrain in response to amphetamine exposure and withdrawal. Findings showed significant increases in glutamate receptor gene expression at both one and 21 days after withdrawal.
49) Boikess SR, O’Dell SJ, Marshall JF. A sensitizing d-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon. Neuroscience Letters. 2010;469(1):49-54. PubMed Link
In this rat study, researchers investigated synaptic protein expression in the diencephalon part of the brain one month after discontinuing amphetamine. Results showed differences from controls in some, but not all areas of the diencephalon. Authors concluded that amphetamine use does alter the brain even after medication is discontinued, and changes may occur more in excitatory synapses.
50) Murray RC, Hebbard JC, Logan AS, Vanchipurakel GA, Gilbert YE, Horner KA. Stress and withdrawal from d-amphetamine alter 5-HT2A receptor mRNA expression in the prefrontal cortex. Neuroscience Letters. 2014;559:44-9. PubMed Link
In this rat study, researchers measured the effects of both withdrawal from amphetamine and stress, induced by a forced swim test, on serotonin receptor gene expression at 24 hours and four days post withdrawal. Findings showed that 24 hours after withdrawal, rats had decreased expression of the serotonin receptor gene than controls, with no impact based on the forced swim test. But, at 4 days, withdrawn rats showed higher levels of expression than controls, and levels were lowered by the forced swim test. The authors concluded that stress can prolong decreased serotonin functioning caused by withdrawal.
51) Renard GM, Sotomayor‐Zarate R, Blanco EH, Gysling K. Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum. Journal of Neuroscience Research. 2014;92(7):937-43. PubMed Link
In this rat study, researchers investigated the impact of amphetamine withdrawal on dopamine transmission in the lateral septum, a part of the brain thought to be involved in addiction. The researchers found decreased release of dopamine in the lateral septum, but not decreased levels of dopamine in the tissue for the 14 day duration of the observation period. The authors hypothesized that the decrease in dopamine release is caused by decreased dopamine reuptake during withdrawal.
Using Rat Model for Schizophrenia
52) Murphy CA, Fend M, Russig H, Feldon J. Latent inhibition, but not prepulse inhibition, is reduced during withdrawal from an escalating dosage schedule of amphetamine. Behavioral neuroscience. 2001;115(6):1247. PubMed Link
In this rat model for schizophrenia, researchers investigated amphetamine withdrawal symptoms. Rats were exposed to amphetamine for 6 days and tested up to four weeks after withdrawal. Results showed that expression of latent inhibition was eliminated during the withdrawal period, which they interpreted as potential evidence of a depressive state caused by withdrawal.
53) Russig H, Murphy CA, Feldon J. Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine. Psychopharmacology. 2003;169(3-4):340-53. PubMed Link
In this rat model for schizophrenia, researchers studied effects of amphetamine withdrawal on prepulse inhibition, where exposure to a previous moderate-intensity stimulus decreases responsiveness to a later, higher-intensity stimulus. Researchers observed rats for up to 60 days post-withdrawal and did not find a difference in their prepulse inhibition compared to control rats. They did find a short-term decreased acoustic startle response and disruptions in latent inhibition.
54) Peleg-Raibstein D, Sydekum E, Feldon J. Differential effects on prepulse inhibition of withdrawal from two different repeated administration schedules of amphetamine. International Journal of Neuropsychopharmacology. 2006;9(6):737-49. PubMed Link
In this rat model for schizophrenia, researchers investigated the effects of withdrawal from amphetamine at two different dosing schedules on behavior and brain monoamine levels. The researchers found that the rats that were given higher doses of amphetamine had reduced dopamine levels in the caudate putamen part of the brain 55 days after withdrawal.
55) Selemon LD, Begović A, Goldman-Rakic PS, Castner SA. Amphetamine sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons in the non-human primate. Neuropsychopharmacology. 2007;32(4):919-31. PubMed Link
In this model of schizophrenia using rhesus monkeys, researchers exposed young adult monkeys to amphetamine for 6 or 12 weeks and studied changes in their brains 3 to 3.5 years after discontinuing amphetamine. Their findings suggested long-lasting degeneration of pyramidal dendrites in the prefrontal cortex.
Withdrawal Symptoms
Studies have been conducted to learn about the effects of withdrawal from stimulant drugs when being used recreationally or abused. Although these studies can provide information on potential withdrawal symptoms when discontinuing ADHD medication, it is important to note that stimulants used recreationally are often at higher doses and frequencies, as well as via different routes (such as injected, snorted, or smoked versus swallowing pills). Therefore, withdrawal effects from recreational use or abuse may be stronger than from prescription use. The most common withdrawal symptoms found in these studies were fatigue, altered sleep patterns, and depression.
56) Monroe RR, Drell HJ. Oral use of stimulants obtained from inhalers. Journal of the American Medical Association. 1947;135(14):909-15. PubMed Link
Authors studied inhaler misuse of amphetamines. Survey results from 264 inmates indicated the most common withdrawal effects were feeling tired, sleeping, shaking hands, and feeling sick to one’s stomach.
57) Oswald I, Thacore VR. Ampehtamine and phenmetrazine addiction: Physiological abnormalities in the abstinence syndrome. Br Med J, 1963;2(5354):427-31. PubMed Link
Authors studied six individuals with amphetamine addictions to assess the effect of withdrawal on sleep patterns. Withdrawal from the drug resulted in a large increase in REM sleep. Return to normal sleep patterns took up to eight weeks. Subjects also reported listlessness, depression, and sleepiness.
58) Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: Affective state, sleep patterns, and MHPG excretion. American Journal of Psychiatry. 1972;129(3):263-9. PubMed Link
Authors studied four subjects who had been using moderately high doses of amphetamines for at least five months and wanted to discontinue their use. Results showed that subjects became depressed during drug withdrawal, most severely in the first few days, but persisting up to several months. Depression was positively related to increased REM sleep and decreased urine excretion of MHPG, a metabolite of norepinephrine, suggesting decreased levels of norepinephrine in the brain.
59) Gossop MR, Bradley BP, Brewis RK. Aphetamine withdrawal and sleep disturbance. Drug and Alcohol Dependence, 1982;10(2):177-83. PubMed Link
Authors studied sleep patterns in 20 amphetamine dependent individuals during drug withdrawal in a hospital setting for 20 days. Results showed an initial period of over-sleeping followed by a longer period of under-sleeping. Amphetamine users also had more variability in their sleep patterns than the control group.
60) Tuma TA. Depressive stupor following amphetamine withdrawal. British Journal of Hospital Medicine. 1993;49(5):361-3. PubMed Link
Author provided case studies of three men in Saudi Arabia who presented at a hospital after discontinuing recreational use of amphetamine. The author described depressive symptoms that all three men experienced and concluded that amphetamine withdrawal can cause a depressive stupor when the drug was taken for long periods.
61)Thompson P, Gillin J, Golshan S, Irwin M. Polygraphic sleep measures differentiate alcoholics and stimulant abusers during short-term abstinence. Biological Psychiatry. 1995;38(12):831-836. PubMed Link
Authors compared sleep patterns of individuals withdrawing from stimulants (amphetamines or cocaine) and alcohol. Results showed that individuals who abuse stimulants slept more and had more REM sleep during the first 10 days of withdrawal than days 11-14. Compared to controls, stimulant users had similar amounts of sleep during the first 10 days, but below normal amounts of sleep during days 11-14.
62) Cantwell B, McBride AJ. Self detoxication by amphetamine dependent patients: A pilot study. Drug and Alcohol Dependence. 1998;49(2):157-63. PubMed Link
Authors interviewed fifty current or past amphetamine dependent clients about previous attempts to stop using amphetamines. All but two subjects injected amphetamines intravenously. Eighty six percent of subjects reported symptoms of withdrawal with the most common symptoms being irritability, aches and pains, feeling depressed, and impaired social functioning. Subjects reported that the symptoms lasted up to three weeks.
63) Schuckit MA, Daeppen JB, Danko GP, Tripp ML, Smith TL, Li TK, Hesselbrock VM, Bucholz KK. Clinical implications for four drugs of the DSM-IV distinction between substance dependence with and without a physiological component. American Journal of Psychiatry. 1999;156(1):41-9. PubMed Link
Authors interviewed individuals diagnosed with substance dependence. Results showed that 87% of subjects identified as amphetamine-dependent experienced withdrawal effects.
Discontinuation Success Rates
Very few studies have explicitly explored how to come off of ADHD medications and withdrawal side effects in humans. The studies that have been done do not suggest there is a strong difference between tapering or abruptly discontinuing ADHD medications.
64) Wernicke JF, Adler L, Spencer T, West SA, Allen AJ, Heiligenstein J, Milton D, Ruff D, Brown WJ, Kelsey D, Michelson D. Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment. J Clin Psychopharmacol. 2004;24(1):30-35. doi: 10.1097/01.jcp.0000104907.75206.c2. PubMed Link
Researchers investigated the potential for discontinuation syndrome of atomoxetine in children and adults diagnosed with ADHD, who had been taking the medication for 9-10 weeks and then discontinued the medication all at once. Results showed that subjects had worsening of ADHD symptoms, but not to pretreatment levels. Researchers did not find evidence of a discontinuation syndrome and determined atomoxetine can be safely discontinued, and tapering is not necessary.
65) Kisicki JC, Fiske K, Lyne A. Phase I, Double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years. Clinical Therapeutics. 2007;29(9):1967-1979. doi: l0.1016/j.clinthera.2007.09.020. PubMed Link
Researchers investigated the effects of abrupt cessation versus taper-down of guanfacine ER on blood pressure. Researchers did not find significant differences in blood pressure for abrupt cessation compared to taper-down. Both treatment groups had a significantly greater decrease in systolic blood pressure than the placebo group by the first day that medication was reduced/withdrawn, but it was no longer significant at the end of the trial. The most common side effects were headache, dry mouth, and fatigue in the abrupt cessation group and dry mouth in the taper-down group.
Conclusion
In sum, the animal research suggests that there are a number of withdrawal effects when discontinuing from stimulant drugs. However, this evidence is limited as results from animal studies are difficult to translate into effects for humans and most of the animal research is mimicking abusive levels of stimulant drugs rather than prescribed doses that are common when treating ADHD. Human studies on withdrawing from stimulants for recreational use have similar findings as animal studies and outline a number of withdrawal effects, primarily fatigue, altered sleep patterns, and depression. Because individuals who abuse stimulants are often taking higher, more frequent doses of the drug, their withdrawal symptoms are most likely more severe than individuals withdrawing from prescription doses. There is very limited research in humans on the effects of coming off ADHD prescription medication, or studies that could provide information on how to come off the medication. However, compared to other psychiatric medications, ADHD medications appear easier to discontinue with less severe withdrawal effects.
Thank You Ms Peters and MIA.
By Shannon Peters December 19, 2016
Editor’s note: We know that our reviews of the withdrawal literature are incomplete, and we urge readers to help us add to these withdrawal reviews. Please send study citations that are relevant to the withdrawal literature for stimulants to rwhitaker@madinamerica.com.
Introduction
Much of the research on withdrawal from stimulant drugs is focused on the effects of withdrawal from recreational use or abuse of these drugs, as opposed to modeling discontinuation of these drugs following treatment for ADHD. This is true of both the animal studies and human studies. Nevertheless, this research literature provides insight into how stimulant use changes the brain; possible long-lasting behavioral effects from such brain changes, and withdrawal symptoms.
Mechanism of Action and Drug-Induced Compensatory Response
Both stimulants and non-stimulants are prescribed to treat ADHD. Stimulant medications are the most commonly prescribed, and are of two classes: amphetamines and methylphenidate. The amphetamines include mixed amphetamine salts (Adderall), dextroamphetamine (Dexedrine), and lisdexamfetamine (Vyanse). Amphetamines increase the amount of norepinephrine, serotonin, and dopamine in the brain by increasing the neuronal release of these neurotransmitters into the synaptic cleft (the tiny gap between neurons.)
The methylphenidate stimulants include Ritalin, Concerta, and Daytrana, and also dexmethylphenidate (Focalin). Methlyphenidates increase dopamine and norepinephrine activity in the brain by blocking their reuptake from the synaptic cleft. The neurotransmitters thus remain longer than normal in the synaptic cleft.
There are also two classes of non-stimulants for ADHD. Atomoxetine (Strattera) inhibits the reuptake of norepinephrine, and thus increases norepinephrine activity in the brain. The second class of non-stimulants are alpha adrenergic agents, such as guanfacine (Intuniv) and clonidine (Kapvay). Alpha adrenergic agents mimic epinephrine and norepinephrine and stimulate the same receptors as these neurotransmitters.
Given that these drugs increase dopamine and norepinephrine activity, they trigger compensatory responses in the brain that, in one way or another, alter this activity. These compensatory changes may include a change in the density of dopamine and norepinephrine receptors; a decrease in the production and release of these molecules by the presynaptic neurons; and changes in the density of transporter molecules involved in the reuptake of the neurotransmitters from the synaptic cleft.
Animal Studies
There is an abundance of animal research on the effects of withdrawal from stimulant drugs, mainly in the form of rat studies. Many of these studies focus on the effect of medications during adolescence on later drug abuse, with contradictory findings. However, in general, the animal studies on stimulant drug withdrawal strongly suggest that the drug exposure leads to a number of both short-term and long-lasting behavioral effects and brain changes.
Models of brain changes follow withdrawal from ADHD medications
Barr JL, Renner KJ, Forster GL. Withdrawal from chronic amphetamine produces persistent anxiety-like behavior but temporally-limited reductions in monoamines and neurogenesis in the adult rat dentate gyrus. Neuropharmacology. 2010;59(6):395-405. PubMed Link
In this study, researchers exposed adult male rats to amphetamine for two weeks and monitored them for four weeks of withdrawal. Results showed that rats had increased anxiety behaviors during withdrawal. The rats’ corticosterone levels were unchanged. Their norepinephrine and serotonin levels in the dentate gyrus of the brain were reduced immediately following treatment, showing evidence of reduced neurogenesis, or new neuron growth, but the levels did not remain low by the end of the study.
2) Sadasivan S, Pond BB, Pani AK, Qu C, Jiao Y, Smeyne RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One. 2012;7(3):e33693. PubMed Link
Researchers administered methylphenidate at two doses to rats for 90 days during the developmental period that matches adolescence and young adulthood in humans, and studied the effects on the brain seven days after withdrawal. Researchers found increased levels of dopamine in the striatum for the lower dose, but not higher dose, of methylphenidate. The authors concluded that long-term therapeutic doses of methylphenidate can have long-term degenerating effects in the brain.
3) Somkuwar SS, Kantak KM, Dwoskin LP. Effect of methylphenidate treatment during adolescence on norepinephrine transporter function in orbitofrontal cortex in a rat model of attention deficit hyperactivity disorder. Journal of Neuroscience Methods. 2015;252:55-63. PubMed Link
Researchers orally exposed rats to methylphenidate from early to late adolescence and then discontinued the drug. Researchers found that during treatment, rats exposed to methylphenidate had lower than normal rates of norepinephrine reuptake. and considered this a normalization of the norepinephrine transporter through treatment. Three to five weeks after discontinuation, norepinephrine transporter function remained at this lower rate which the researchers concluded as persisting treatment effects even after drug discontinuation.
Impacts of ADHD medication treatment and withdrawal on later drug use
4) Brandon CL, Marinelli M, Baker LK, White FJ. Enhanced reactivity and vulnerability to cocaine following methylphenidate treatment in adolescent rats. Neuropsychopharmacology. 2001;25(5):651-61. PubMed Link
Researchers exposed rats to methylphenidate during adolescence, withdrew the drug, and then studied rats’ behavior toward cocaine as adults. Findings showed that rats exposed to low doses, but not moderate doses, of methylphenidate engaged in more cocaine self-administration. Researchers concluded that early exposure to low doses of methylphenidate may increase susceptibility to low doses of cocaine, and consequently increase risk of cocaine use as adults.
5) Andersen SL, Arvanitogiannis A, Pliakas AM, LeBlanc C, Carlezon WA. Altered responsiveness to cocaine in rats exposed to methylphenidate during development. Nature Neuroscience. 2002;5(1):13-4. PubMed Link
Researchers exposed pre-adolescent rats to methylphenidate and then withdrew the drug in order to study its effects on the rats’ responsiveness to cocaine in adulthood. They found that the rats were less responsive to cocaine’s rewarding effects and concluded that pre-adolescent exposure to methylphenidate may cause lasting changes to dopaminergic function. The researchers also studied rats exposed to methylphenidate in adulthood and concluded that neurobiological effects differ depending on the developmental stage when rats are exposed to the medication.
6) Carlezon WA, Mague SD, Andersen SL. Enduring behavioral effects of early exposure to methylphenidate in rats. Biological Psychiatry. 2003;54(12):1330-7. PubMed Link
In this study, researchers examined how exposure to methylphenidate or cocaine in preadolescence affected behaviors in adult rats. Researchers found that exposure to methylphenidate in preadolescence can cause behavioral changes in adulthood including finding cocaine less rewarding and demonstrating depressive-like symptoms.
7) Mague SD, Andersen SL, Carlezon WA. Early developmental exposure to methylphenidate reduces cocaine-induced potentiation of brain stimulation reward in rats. Biological Psychiatry. 2005;57(2):120-5. PubMed Link
Researchers exposed rats to methylphenidate during pre-adolescence, withdrew the drug, and then studied the impacts on cocaine’s ability to simulate the reward system in the brain. The authors found that early exposure to methylphenidate resulted in a decreased effect of cocaine on the reward system, suggesting that the dopamine system functioned in an abnormal manner.
8) Augustyniak PN, Kourrich S, Rezazadeh SM, Stewart J, Arvanitogiannis A. Differential behavioral and neurochemical effects of cocaine after early exposure to methylphenidate in an animal model of attention deficit hyperactivity disorder. Behavioural Brain Research. 2006;167(2):379-82. PubMed Link
Researchers exposed pubertal rats to methylphenidate and then withdrew the drug to examine its effects on cocaine use and dopamine levels in adulthood. The researchers found that the exposure reduced the rats’ sensitivity to cocaine in adulthood, but did not alter the dopamine system in the mesolimbic brain pathway.
9) Gill KE, Pierre PJ, Daunais J, Bennett AJ, Martelle S, Gage HD, Swanson JM, Nader MA, Porrino LJ. Chronic treatment with extended release methylphenidate does not alter dopamine systems or increase vulnerability for cocaine self-administration: a study in nonhuman primates. Neuropsychopharmacology. 2012;37(12):2555-65. PubMed Link
In this rhesus monkey model for ADHD treatment, monkeys were given methylphenidate for a year and studied 3-5 months after discontinuation of treatment. Findings showed that methylphenidate-treated monkeys had unchanged levels of specific dopamine receptor, D2/D3, while controls had a decreasing number of receptors (a decrease of receptors in this context is seen as a developmental process of synaptic pruning). The authors found no evidence that methylphenidate increases vulnerability to cocaine later in life.
10) Somkuwar SS, Jordan CJ, Kantak KM, Dwoskin LP. Adolescent atomoxetine treatment in a rodent model of ADHD: effects on cocaine self-administration and dopamine transporters in frontostriatal regions. Neuropsychopharmacology. 2013;38(13):2588-97. PubMed Link
Researchers exposed rats to atomoxetine during adolescence, withdrew the drug, and then studied the impacts on cocaine self-administration and on dopamine and norepinephrine transporters. Findings showed that atomoxetine did not increase vulnerability to cocaine and authors concluded that atomoxetine may be a better treatment choice than methylphenidate when the prescriber is worried about drug abuse.
11) Jordan CJ, Harvey RC, Baskin BB, Dwoskin LP, Kantak KM. Cocaine-seeking behavior in a genetic model of attention-deficit/hyperactivity disorder following adolescent methylphenidate or atomoxetine treatments. Drug and Alcohol Dependence. 2014;140:25-32. PubMed Link
Researchers exposed rats to methylphenidate and atomoxetine during adolescence, withdrew the drug, and then studied rats’ cocaine-seeking behavior as adults. Results showed that adult rats previously treated with methylphenidate had increased cocaine intake, but there was no increase in cocaine intake for rats previously treated with atomoxetine. Neither drug resulted in increases in cocaine seeking in adulthood.
12) Jordan CJ, Taylor DM, Dwoskin LP, Kantak KM. Adolescent D-amphetamine treatment in a rodent model of ADHD: Pro-cognitive effects in adolescence without an impact on cocaine cue reactivity in adulthood. Behavioural Brain Research. 2016;297:165-79. PubMed Link
Researchers exposed rats to d-amphetamine during adolescence, withdrew the drug, and then studied rats’ cocaine-seeking behavior as adults. The findings showed that d-amphetamine exposure during adolescence did not change self-administration of cocaine and decreased cocaine-seeking behavior in adulthood. The authors concluded that treatment with d-amphetamine may result in lower risk of future cocaine use than methylphenidate treatment.
Behavioral impacts of withdrawal
13) Herman ZS, Trzeciak H, Chruściel TL, Kmieciak-Kołada K, Drybański A, Sokoła A. The influence of prolonged amphetamine treatment and amphetamine withdrawal on brain biogenic amine content and behaviour in the rat. Psychopharmacologia. 1971;21(1):74-81. PubMed Link
Researchers exposed rats to D–L-amphetamine sulphate for 9 months and studied the behavioral effects of the drug and drug withdrawal. Authors found that, during withdrawal, rats moved around less (measured for 12 days post-withdrawal) and had lower levels of noradrenaline and serotonin in the cerebellum part of the brain (measured at 3 days post-withdrawal).
14) Leith NJ, Barrett RJ. Amphetamine and the reward system: evidence for tolerance and post-drug depression. Psychopharmacologia. 1976;46(1):19-25. PubMed Link
In this study, researchers measured the effects of withdrawal from d-amphetamine on self-electrical brain stimulation, examining effects on the reward system in the brain. One day after d-amphetamine withdrawal, rats had reduced self-stimulation, which the authors interpreted as dysregulation in the brain’s reward system and depression.
15) Schreiber H, Bell R, Conely L, Kufner M, Palet J, Wright L. Diminished reaction to a novel stimulus during amphetamine withdrawal in rats. Pharmacology Biochemistry and Behavior. 1976;5(6):687-90. PubMed Link
Researchers examined the effects of d-amphetamine withdrawal on response to a new stimulus. Rats were exposed to two doses of d-amphetamine or saline for eight days and tested one day after discontinuing the drug. Findings showed that rats exposed to more d-amphetamine had the least response to a new stimulus and rats exposed to the smaller dose of d-amphetamine had less response than control rats.
16) Simpson DM, Annau Z. Behavioral withdrawal following several psychoactive drugs. Pharmacology Biochemistry and Behavior. 1977;7(1):59-64. PubMed Link
In this rat study, researchers assessed behavioral withdrawal from four types of psychoactive drugs, including amphetamine, by measuring self-electrical stimulation of the brain. Findings showed that rats exposed to amphetamine had increased rates of self-stimulation while on the drug, but decreased their self-stimulation during withdrawal.
17) Cassens G, Actor C, Kling M, Schildkraut JJ. Amphetamine withdrawal: Effects on threshold of intracranial reinforcement. Psychopharmacology. 1981;73(4):318-22. PubMed Link
In this rat study, researchers examined the effects of withdrawal from d-amphetamine on the threshold to activate the reward system in the brain. Results showed an increased threshold, meaning rats found a stimulus less rewarding than control rats, within 24 hours of withdrawal, with the highest threshold increase around 24 to 72 hours.
18) Kokkinidis L, Zacharko RM, Anisman H. Amphetamine withdrawal: A behavioral evaluation. Life sciences. 1986;38(17):1617-23. PubMed Link
In this study, researchers exposed mice to amphetamines for 10 days and studied the behavioral effects of withdrawal 24 hours after the mice’s last exposure to amphetamine. Results showed that withdrawn mice responded less to electrical stimulation in the brain, and moved less in the forced swim test. However, withdrawn mice did not differ from controls on behaviors in the shuttle escape task or acoustic startle reflex. The authors concluded that depressive behaviors induced by amphetamine withdrawal are due more to motivation than mechanisms of motor-activity or arousal.
19) Paulson PE, Camp DM, Robinson TE. Time course of transient behavioral depression and persistent behavioral sensitization in relation to regional brain monoamine concentrations during amphetamine withdrawal in rats. Psychopharmacology. 1991;103(4):480-92. PubMed Link
In this rat study, researchers investigated the withdrawal syndrome for d-amphetamine. Researchers found that withdrawn rats showed depressive behaviors as soon as two days post-withdrawal, but the behaviors were gone by one month. Depressive behaviors were associated with short-term lower levels of norepinephrine in the hypothalamus part of the brain.
20) Schindler CW, Persico AM, Uhl GR, Goldberg SR. Behavioral assessment of high-dose amphetamine withdrawal: importance of training and testing conditions. Pharmacology Biochemistry and Behavior. 1994;49(1):41-6. PubMed Link
In this rat study, researchers investigated the effects of withdrawal from chronic (2 weeks) versus acute (one time) d-amphetamine use. Results showed that chronic rats engaged in less movement in a locomotor activity test 24-54 hours after withdrawal, and engaged in less movement during a swim test 36-72 hours after withdrawal.
21) Wise RA, Munn E. Withdrawal from chronic amphetamine elevates baseline intracranial self-stimulation thresholds. Psychopharmacology. 1995;117(2):130-6. PubMed Link
In this rat study, researchers measured self-stimulation of the lateral hypothalamus in the brain after withdrawal from amphetamine. Rats were exposed to amphetamine for six weeks and self-stimulation was measured starting at 36 hours post-withdrawal up to three weeks. Authors found that drug withdrawn rats engaged in self-stimulation less frequently and had higher thresholds, meaning they required a stronger stimulus to engage in self-stimulation. By two weeks after drug discontinuation, amphetamine exposed rats did not differ from control rats.
22) Barr AM, Phillips AG. Withdrawal following repeated exposure to d-amphetamine decreases responding for a sucrose solution as measured by a progressive ratio schedule of reinforcement. Psychopharmacology. 1999;141(1):99-106. PubMed Link
In this rat study, researchers investigated whether withdrawal from d-amphetamine after four days of exposure reduced rats’ effort for a natural reward of sugar water. Results showed that rats withdrawing from the drug were less motivated to obtain a natural reward.
23) Barr AM, Fiorino DF, Phillips AG. Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat. Pharmacology Biochemistry and Behavior. 1999;64(3):597-604. PubMed Link
In this rat study, researchers investigated the impact of withdrawal from d-amphetamine on sexual behavior in male rats. Rats were exposed to d-amphetamine for four days and tested 12 hours after final dose. The results showed decreased motivation in preparatory sexual behaviors, but no change in consummatory behaviors.
24) Barr AM, Phillips AG. Increased successive negative contrast in rats withdrawn from an escalating-dose schedule of D-amphetamine. Pharmacology Biochemistry and Behavior. 2002;71(1):293-9. PubMed Link
In this rat study, researchers examined the effects of withdrawal from d-amphetamine on behavior by measuring their consumption of sugar water compared to rats not exposed to the drug. Findings showed rats withdrawn from d-amphetamine that were previously given 34% sugar water and then given 4% sugar water consumed much less than controls for up to 60 hours. The authors understood this behavior to be connected to higher emotionality during withdrawal.
25) Russig H, Durrer A, Yee BK, Murphy CA, Feldon J. The acquisition, retention and reversal of spatial learning in the Morris water maze task following withdrawal from an escalating dosage schedule of amphetamine in Wistar rats. Neuroscience. 2003;119(1):167-79. PubMed Link
In this rat study, researchers examined the effects of d-amphetamine withdrawal on spatial learning using the Morris water maze task. Researchers found that rats withdrawing from amphetamine had enhanced reversal learning (learning to locate a new place in the water maze) than control rats.
26) Cryan JF, Hoyer D, Markou A. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biological Psychiatry. 2003;54(1):49-58. PubMed Link
In this rat study, researchers investigated behavioral effects of amphetamine withdrawal. Findings showed a number of changes in behavior that reflect depressive symptoms including higher thresholds to activate reward system, less swimming and climbing behaviors in a forced swim test, and less movement in a mouse tail suspension test, lasting for the 72 hours of observation.
27) Peterson JD, Wolf ME, White FJ. Impaired DRL 30 performance during amphetamine withdrawal. Behavioural Brain Research. 2003;143(1):101-8. PubMed Link
In this rat study, researchers measured impulsivity during amphetamine withdrawal by measuring rats’ ability to wait at least 30 seconds to poke a hole with their nose in order to receive food. Rats were exposed to amphetamine for five days and then withdrawn from amphetamine for three days before testing began. Researchers found amphetamine withdrawn rats had more nose pokes than controls, demonstrating higher rates of impulsivity, for up to two weeks after withdrawal.
28) Che Y, Cui YH, Tan H, Andreazza AC, Young LT, Wang JF. Abstinence from repeated amphetamine treatment induces depressive-like behaviors and oxidative damage in rat brain. Psychopharmacology. 2013;227(4):605-14. PubMed Link
In this rat study, researchers explored causes of depressive symptoms in amphetamine withdrawal. Results showed that rats demonstrated depressive symptoms during withdrawal and that withdrawal caused oxidative damage in the brain.
Physiological Impacts of Withdrawal
29) Lynch MA, Leonard BE. Changes in brain γ-aminobutyric acid concentrations following acute and chronic amphetamine administration and during post amphetamine depression. Biochemical pharmacology. 1978;27(14):1853-5. PubMed Link
In this rat study, researchers investigated changes of GABA, an inhibitory neurotransmitter, in different parts of the brain from d-amphetamine exposure and withdrawal. After an increase in GABA during administration of the drug, researchers found that GABA levels decreased to normal levels compared to the control group within 7 days of withdrawal in the striatum and brain stem. They also found that GABA levels in the amygdala increased during withdrawal. The authors described the rats as behaviorally depressed during withdrawal.
30) Cassens G, Kuruc A, Orsulak PJ, Schildkraut JJ. Amphetamine withdrawal: effects on brain levels of MHPG-SO4 in the rat. Communications in psychopharmacology. 1979;3(4):217. PubMed Link
In this rat study, researchers measured brain levels of a metabolite of norepinephrine, MHPG-SO4, after withdrawal from d-amphetamine. The authors found that up to 48 hours after withdrawal, rats had decreased MHPG-SO4 levels.
31) Koike Y, Togashi H, Shimamura K, Yomaida I, Saito H. Effects of abrupt cessation of treatment with clonidine and guanfacine on blood pressure and heart rate in spontaneously hypertensive rats. Clinical and experimental hypertension. 1981;3(1):103-20. PubMed Link
In this rat study, authors researched the impact of guanfacine withdrawal on blood pressure. Rats had low blood pressure while exposed to 5 weeks of guanfacine, and abrupt discontinuation of the medication did not result in a fast rise in blood pressure.
32) Ricaurte G, Seiden LS, Schuster C. Further evidence that amphetamines produce long-lasting dopamine neurochemical deficits by destroying dopamine nerve fibers. Brain Research. 1984;303(2):359-64. PubMed Link
In this rat study, researchers administered either methamphetamine or amphetamine to rats for three days and then studied the effects on the brain two weeks after withdrawal. The authors found decreased levels of dopamine and evidence of nerve fiber degeneration in the striatum.
33) Swerdlow NR, Hauger R, Irwin M, Koob GF, Britton KT, Pulvirenti L. Endocrine, immune, and neurochemical changes in rats during withdrawal from chronic amphetamine intoxication. Neuropsychopharmacology. 1991;5(1):23-31. PubMed Link
In this rat study, researchers examined the impacts of withdrawal from 10-day amphetamine exposure. The researchers found that adrenocorticotropic hormone and corticosterone levels, which are normally correlated, uncoupled by the fifth day of withdrawal, with the effect persisting for the 10 days of observation. They also found decreased levels of dopamine and its metabolite, DOPAC, in certain brain regions. The researchers concluded this represented dysregulation in the hypothalamic–pituitary–adrenal axis.
34) Rossetti ZL, Hmaidan Y, Gessa GL. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats. European Journal of Pharmacology. 1992;221(2-3):227-34. PubMed Link
In this rat study, authors investigated the effects on dopamine levels in the brain for a number of drugs that are frequently abused. The authors found that with amphetamine withdrawal, dopamine levels decreased quickly, to about 50% of control levels in the first day, and remained low for several days, and then return to levels equivalent to controls within 10 days.
35) Persico AM, Schindler CW, Brannock MT, Gonzalez AM, Surratt CK, Uhl GR. Dopaminergic gene expression during amphetamine withdrawal. Neuroreport. 1993;4(1):41-4. PubMed Link
In this rat study, researchers studied the effects of amphetamine withdrawal on gene expression that affects dopamine. The researchers did not find changes in dopaminergic gene expression, but found a slight increase in tyrosine hydroxylase gene expression and substantially decreased expression of a specific amine transporter, both of which are involved in dopamine transmission. The authors concluded that these changes in gene expression may be involved in restoring the balance of dopamine in the brain.
36) Persico AM, Schindler CW, Zaczek R, Brannock MT, Uhl GR. Brain transcription factor gene expression, neurotransmitter levels, and novelty response behaviors: alterations during rat amphetamine withdrawal and following chronic injection stress. Synapse. 1995;19(3):212-27. PubMed Link
In this rat study, researchers explored the effects of withdrawal from amphetamine on transcription factors that impact neurotransmitter gene expression in the brain. Findings showed decreased transcription factor and decreased dopamine levels in areas of the brain within 12 hours of withdrawal. The levels returned to normal, compared to control, by 54 hours.
37) Paulson PE, Robinson TE. Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum: analysis of circadian patterns using automated on-line microdialysis. Neuropsychopharmacology. 1996;14(5):325. PubMed Link
In this rat study, researchers explored behavioral symptoms and their connection to dopamine concentration in different brain regions during circadian rhythms at 3, 7, and 28 days post amphetamine withdrawal. Rats displayed depressive behaviors within a week of drug discontinuation and at 3 and 7 days post-withdrawal, rats had decreases in dopamine in the dorsolateral caudate nucleus. At 28 days, rats no longer presented with depressive behaviors and dopamine levels increased in the caudate and accumbens parts of the brain.
38) Melega WP, Raleigh MJ, Stout DB, Huang SC, Phelps ME. Ethological and 6-[18F] fluoro-L-DOPA-PET profiles of long-term vulnerability to chronic amphetamine. Behavioural Brain Research. 1997;84(1):259-68. PubMed Link
In this study on vervet monkeys, researchers used PET scans to measure dopamine function in the striatum of the brain. The researchers administered amphetamine to the monkeys to increase dopamine function, and then withdrew the drug after ten days. Findings showed that monkeys slowly recovered baseline dopamine functioning after 24 months of drug discontinuation.
39) Robinson TE, Kolb B. Persistent structural modifications in nucleus accumbens and prefrontal cortex neurons produced by previous experience with amphetamine. The Journal of Neuroscience. 1997;17(21):8491-7. PubMed Link
In this rat study, researchers examined the changes in the brain caused by exposure to amphetamine for a month after discontinuing the drug. They found a number of structural changes to neurons in specific parts of the brain that affect communication between neurons and hypothesized that these changes are connected to behavioral changes seen in humans after withdrawal from amphetamine abuse.
40) Raheem KA, Ismael N, Saad A, El-Sayad S. Gluconeogenic activity in response to chronic administration of amphetamine sulphate and drug withdrawal. General Pharmacology: The Vascular System. 1997;29(4):687-90. PubMed Link
In this rat study, researchers explored the impact of chronic amphetamine use and withdrawal on serum levels. Results showed that rats that discontinued amphetamine after four weeks of use had glucose levels close to controls, and glutamate oxaloacetic transaminase (GOT) enzyme activity returned to normal, but corticosterone levels remained elevated during 30 hours of studied withdrawal. The authors conclude rats can recover from the effects of amphetamine after withdrawing from the drug.
41) Lu W, Monteggia LM, Wolf ME. Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex. European Journal of Neuroscience. 1999;11(9):3167-77. PubMed Link
In this rat study, researchers investigated whether NMDA receptors, a neuron receptor for the neurotransmitter glutamate, were altered by amphetamine use even after withdrawal. The researchers did not find changes in a subunit of the NMDA receptor after three days of withdrawal, but found decreased expression of the subunit of the receptor 14 days after withdrawal. The authors hypothesized that this may signify reduced excitation in dopaminergic neurons.
42) Onn SP, Grace AA. Amphetamine withdrawal alters bistable states and cellular coupling in rat prefrontal cortex and nucleus accumbens neurons recorded in vivo. The Journal of Neuroscience. 2000;20(6):2332-45. PubMed Link
In this rat study, researchers explored changes in gap junction functioning, a type of communication between neurons, in the corticoaccumbens network after withdrawal from amphetamine. Researchers found changes in gap junction function 28 days after withdrawal.
43) Murphy CA, Russig H, Pezze MA, Ferger B, Feldon J. Amphetamine withdrawal modulates FosB expression in mesolimbic dopaminergic target nuclei: effects of different schedules of administration. Neuropharmacology. 2003;44(7):926-39. PubMed Link
In this rat study, researchers investigated the effects on gene expression of withdrawal from a low dose compared to a moderately high dose of amphetamine. Findings showed an increased expression of the FosB gene only in the higher dose. The authors concluded that withdrawal from a higher dose of amphetamine changes gene expression that impacts dopamine, but that does not affect monoamine levels.
44) Kolb B, Gorny G, Li Y, Samaha AN, Robinson TE. Amphetamine or cocaine limits the ability of later experience to promote structural plasticity in the neocortex and nucleus accumbens. Proceedings of the National Academy of Sciences. 2003;100(18):10523-8. PubMed Link
In this rat study, researchers examined the effects of amphetamine and cocaine use on neural plasticity, the ability for the brain to adapt, after 3.5 months of withdrawal. The authors found that rats previously exposed to amphetamine had inhibited neural plasticity when exposed to a complex environment and concluded that even after withdrawal, amphetamine use may lead to persistent behavioral and cognitive deficits.
45) Mohila CA, Onn SP. Increases in the density of parvalbumin-immunoreactive neurons in anterior cingulate cortex of amphetamine-withdrawn rats: evidence for corticotropin-releasing factor in sustained elevation. Cerebral Cortex. 2005;15(3):262-74. PubMed Link
In this rat study, researchers investigated changes to the inhibitory neurotransmitter, GABA’s, signaling in the brain during withdrawal from amphetamines. Researchers concluded that withdrawal from amphetamine alters GABA signaling.
46) McCracken CB, Patel KM, Vrana KE, Paul DL, Roberts D. Amphetamine withdrawal produces region‐specific and time‐dependent changes in connexin36 expression in rat brain. Synapse. 2005;56(1):39-44. PubMed Link
In this rat study, researchers explored changes in gap junction functioning, a type of communication between neurons, after withdrawal from extended amphetamine exposure. Findings showed that during the withdrawal period there were changes in the expression of a gap junction protein, connexin36, in brain regions considered to be involved in sensitization and addiction.
47) Russig H, Pryce CR, Feldon J. Amphetamine withdrawal leads to behavioral sensitization and reduced HPA axis response following amphetamine challenge. Brain Research. 2006;1084(1):185-95. PubMed Link
In this rat study, researchers investigated stress hormone release related to depression-like symptoms during amphetamine withdrawal. Rats were exposed to amphetamine three times a day for three days and withdrawal was studied for 30 days. Results showed no effect of withdrawal on release of adrenocorticotropic hormone or corticosterone in stressful situations.
48) Parelkar NK, Wang JQ. Upregulation of metabotropic glutamate receptor 8 mRNA expression in the rat forebrain after repeated amphetamine administration. Neuroscience Letters. 2008;433(3):250-4. PubMed Link
In this rat study, researchers measured gene expression of glutamate receptors in the forebrain in response to amphetamine exposure and withdrawal. Findings showed significant increases in glutamate receptor gene expression at both one and 21 days after withdrawal.
49) Boikess SR, O’Dell SJ, Marshall JF. A sensitizing d-amphetamine dose regimen induces long-lasting spinophilin and VGLUT1 protein upregulation in the rat diencephalon. Neuroscience Letters. 2010;469(1):49-54. PubMed Link
In this rat study, researchers investigated synaptic protein expression in the diencephalon part of the brain one month after discontinuing amphetamine. Results showed differences from controls in some, but not all areas of the diencephalon. Authors concluded that amphetamine use does alter the brain even after medication is discontinued, and changes may occur more in excitatory synapses.
50) Murray RC, Hebbard JC, Logan AS, Vanchipurakel GA, Gilbert YE, Horner KA. Stress and withdrawal from d-amphetamine alter 5-HT2A receptor mRNA expression in the prefrontal cortex. Neuroscience Letters. 2014;559:44-9. PubMed Link
In this rat study, researchers measured the effects of both withdrawal from amphetamine and stress, induced by a forced swim test, on serotonin receptor gene expression at 24 hours and four days post withdrawal. Findings showed that 24 hours after withdrawal, rats had decreased expression of the serotonin receptor gene than controls, with no impact based on the forced swim test. But, at 4 days, withdrawn rats showed higher levels of expression than controls, and levels were lowered by the forced swim test. The authors concluded that stress can prolong decreased serotonin functioning caused by withdrawal.
51) Renard GM, Sotomayor‐Zarate R, Blanco EH, Gysling K. Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum. Journal of Neuroscience Research. 2014;92(7):937-43. PubMed Link
In this rat study, researchers investigated the impact of amphetamine withdrawal on dopamine transmission in the lateral septum, a part of the brain thought to be involved in addiction. The researchers found decreased release of dopamine in the lateral septum, but not decreased levels of dopamine in the tissue for the 14 day duration of the observation period. The authors hypothesized that the decrease in dopamine release is caused by decreased dopamine reuptake during withdrawal.
Using Rat Model for Schizophrenia
52) Murphy CA, Fend M, Russig H, Feldon J. Latent inhibition, but not prepulse inhibition, is reduced during withdrawal from an escalating dosage schedule of amphetamine. Behavioral neuroscience. 2001;115(6):1247. PubMed Link
In this rat model for schizophrenia, researchers investigated amphetamine withdrawal symptoms. Rats were exposed to amphetamine for 6 days and tested up to four weeks after withdrawal. Results showed that expression of latent inhibition was eliminated during the withdrawal period, which they interpreted as potential evidence of a depressive state caused by withdrawal.
53) Russig H, Murphy CA, Feldon J. Prepulse inhibition during withdrawal from an escalating dosage schedule of amphetamine. Psychopharmacology. 2003;169(3-4):340-53. PubMed Link
In this rat model for schizophrenia, researchers studied effects of amphetamine withdrawal on prepulse inhibition, where exposure to a previous moderate-intensity stimulus decreases responsiveness to a later, higher-intensity stimulus. Researchers observed rats for up to 60 days post-withdrawal and did not find a difference in their prepulse inhibition compared to control rats. They did find a short-term decreased acoustic startle response and disruptions in latent inhibition.
54) Peleg-Raibstein D, Sydekum E, Feldon J. Differential effects on prepulse inhibition of withdrawal from two different repeated administration schedules of amphetamine. International Journal of Neuropsychopharmacology. 2006;9(6):737-49. PubMed Link
In this rat model for schizophrenia, researchers investigated the effects of withdrawal from amphetamine at two different dosing schedules on behavior and brain monoamine levels. The researchers found that the rats that were given higher doses of amphetamine had reduced dopamine levels in the caudate putamen part of the brain 55 days after withdrawal.
55) Selemon LD, Begović A, Goldman-Rakic PS, Castner SA. Amphetamine sensitization alters dendritic morphology in prefrontal cortical pyramidal neurons in the non-human primate. Neuropsychopharmacology. 2007;32(4):919-31. PubMed Link
In this model of schizophrenia using rhesus monkeys, researchers exposed young adult monkeys to amphetamine for 6 or 12 weeks and studied changes in their brains 3 to 3.5 years after discontinuing amphetamine. Their findings suggested long-lasting degeneration of pyramidal dendrites in the prefrontal cortex.
Withdrawal Symptoms
Studies have been conducted to learn about the effects of withdrawal from stimulant drugs when being used recreationally or abused. Although these studies can provide information on potential withdrawal symptoms when discontinuing ADHD medication, it is important to note that stimulants used recreationally are often at higher doses and frequencies, as well as via different routes (such as injected, snorted, or smoked versus swallowing pills). Therefore, withdrawal effects from recreational use or abuse may be stronger than from prescription use. The most common withdrawal symptoms found in these studies were fatigue, altered sleep patterns, and depression.
56) Monroe RR, Drell HJ. Oral use of stimulants obtained from inhalers. Journal of the American Medical Association. 1947;135(14):909-15. PubMed Link
Authors studied inhaler misuse of amphetamines. Survey results from 264 inmates indicated the most common withdrawal effects were feeling tired, sleeping, shaking hands, and feeling sick to one’s stomach.
57) Oswald I, Thacore VR. Ampehtamine and phenmetrazine addiction: Physiological abnormalities in the abstinence syndrome. Br Med J, 1963;2(5354):427-31. PubMed Link
Authors studied six individuals with amphetamine addictions to assess the effect of withdrawal on sleep patterns. Withdrawal from the drug resulted in a large increase in REM sleep. Return to normal sleep patterns took up to eight weeks. Subjects also reported listlessness, depression, and sleepiness.
58) Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: Affective state, sleep patterns, and MHPG excretion. American Journal of Psychiatry. 1972;129(3):263-9. PubMed Link
Authors studied four subjects who had been using moderately high doses of amphetamines for at least five months and wanted to discontinue their use. Results showed that subjects became depressed during drug withdrawal, most severely in the first few days, but persisting up to several months. Depression was positively related to increased REM sleep and decreased urine excretion of MHPG, a metabolite of norepinephrine, suggesting decreased levels of norepinephrine in the brain.
59) Gossop MR, Bradley BP, Brewis RK. Aphetamine withdrawal and sleep disturbance. Drug and Alcohol Dependence, 1982;10(2):177-83. PubMed Link
Authors studied sleep patterns in 20 amphetamine dependent individuals during drug withdrawal in a hospital setting for 20 days. Results showed an initial period of over-sleeping followed by a longer period of under-sleeping. Amphetamine users also had more variability in their sleep patterns than the control group.
60) Tuma TA. Depressive stupor following amphetamine withdrawal. British Journal of Hospital Medicine. 1993;49(5):361-3. PubMed Link
Author provided case studies of three men in Saudi Arabia who presented at a hospital after discontinuing recreational use of amphetamine. The author described depressive symptoms that all three men experienced and concluded that amphetamine withdrawal can cause a depressive stupor when the drug was taken for long periods.
61)Thompson P, Gillin J, Golshan S, Irwin M. Polygraphic sleep measures differentiate alcoholics and stimulant abusers during short-term abstinence. Biological Psychiatry. 1995;38(12):831-836. PubMed Link
Authors compared sleep patterns of individuals withdrawing from stimulants (amphetamines or cocaine) and alcohol. Results showed that individuals who abuse stimulants slept more and had more REM sleep during the first 10 days of withdrawal than days 11-14. Compared to controls, stimulant users had similar amounts of sleep during the first 10 days, but below normal amounts of sleep during days 11-14.
62) Cantwell B, McBride AJ. Self detoxication by amphetamine dependent patients: A pilot study. Drug and Alcohol Dependence. 1998;49(2):157-63. PubMed Link
Authors interviewed fifty current or past amphetamine dependent clients about previous attempts to stop using amphetamines. All but two subjects injected amphetamines intravenously. Eighty six percent of subjects reported symptoms of withdrawal with the most common symptoms being irritability, aches and pains, feeling depressed, and impaired social functioning. Subjects reported that the symptoms lasted up to three weeks.
63) Schuckit MA, Daeppen JB, Danko GP, Tripp ML, Smith TL, Li TK, Hesselbrock VM, Bucholz KK. Clinical implications for four drugs of the DSM-IV distinction between substance dependence with and without a physiological component. American Journal of Psychiatry. 1999;156(1):41-9. PubMed Link
Authors interviewed individuals diagnosed with substance dependence. Results showed that 87% of subjects identified as amphetamine-dependent experienced withdrawal effects.
Discontinuation Success Rates
Very few studies have explicitly explored how to come off of ADHD medications and withdrawal side effects in humans. The studies that have been done do not suggest there is a strong difference between tapering or abruptly discontinuing ADHD medications.
64) Wernicke JF, Adler L, Spencer T, West SA, Allen AJ, Heiligenstein J, Milton D, Ruff D, Brown WJ, Kelsey D, Michelson D. Changes in symptoms and adverse events after discontinuation of atomoxetine in children and adults with attention deficit/hyperactivity disorder: A prospective, placebo-controlled assessment. J Clin Psychopharmacol. 2004;24(1):30-35. doi: 10.1097/01.jcp.0000104907.75206.c2. PubMed Link
Researchers investigated the potential for discontinuation syndrome of atomoxetine in children and adults diagnosed with ADHD, who had been taking the medication for 9-10 weeks and then discontinued the medication all at once. Results showed that subjects had worsening of ADHD symptoms, but not to pretreatment levels. Researchers did not find evidence of a discontinuation syndrome and determined atomoxetine can be safely discontinued, and tapering is not necessary.
65) Kisicki JC, Fiske K, Lyne A. Phase I, Double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years. Clinical Therapeutics. 2007;29(9):1967-1979. doi: l0.1016/j.clinthera.2007.09.020. PubMed Link
Researchers investigated the effects of abrupt cessation versus taper-down of guanfacine ER on blood pressure. Researchers did not find significant differences in blood pressure for abrupt cessation compared to taper-down. Both treatment groups had a significantly greater decrease in systolic blood pressure than the placebo group by the first day that medication was reduced/withdrawn, but it was no longer significant at the end of the trial. The most common side effects were headache, dry mouth, and fatigue in the abrupt cessation group and dry mouth in the taper-down group.
Conclusion
In sum, the animal research suggests that there are a number of withdrawal effects when discontinuing from stimulant drugs. However, this evidence is limited as results from animal studies are difficult to translate into effects for humans and most of the animal research is mimicking abusive levels of stimulant drugs rather than prescribed doses that are common when treating ADHD. Human studies on withdrawing from stimulants for recreational use have similar findings as animal studies and outline a number of withdrawal effects, primarily fatigue, altered sleep patterns, and depression. Because individuals who abuse stimulants are often taking higher, more frequent doses of the drug, their withdrawal symptoms are most likely more severe than individuals withdrawing from prescription doses. There is very limited research in humans on the effects of coming off ADHD prescription medication, or studies that could provide information on how to come off the medication. However, compared to other psychiatric medications, ADHD medications appear easier to discontinue with less severe withdrawal effects.
Thank You Ms Peters and MIA.
Thursday, January 26, 2017
Mental Health First Aid: Another Psychiatric Expansionist Tool
Dr Phil Hickey
On December 25, 2016, the Baltimore Sun published an excellent article titled Drug companies prey on children, by Patrick D. Hahn, PhD. Dr. Hahn is an affiliate professor of biology at Loyola University, Maryland. Here are some quotes:
Please take a look at Dr. Hahn’s article, and pass it on. Mental
Health First Aid is not a good thing. Rather, it is just another
psychiatric expansionist tool.
Continue Reading.
Thank You Dr Hickey
And bookmark Dr Hickey's URL.
On December 25, 2016, the Baltimore Sun published an excellent article titled Drug companies prey on children, by Patrick D. Hahn, PhD. Dr. Hahn is an affiliate professor of biology at Loyola University, Maryland. Here are some quotes:
“I recently attended Youth Mental Health First Aid Training at a local public school. It was an eye-opening experience.”
“Youth Mental Health First Aid Training,
sponsored by the National Council for Behavioral Health, is intended to
enable teachers, parents and others in contact with young people to
identify potential ‘mental illnesses’ in order to facilitate early
detection and treatment by our mental health care system. My fellow
attendees were surprisingly open about their own experiences with that
system. One mentioned that her son became manic after being diagnosed
for ADHD. Another said that both she and her roommate became bipolar
after being diagnosed for depression. Neither our facilitators nor
anyone else present pointed out that mania and bipolar disorder are
toxic effects of medications commonly prescribed for ADHD and
depression.”
“Our training manual didn’t say anything
about this either, although it did claim that depression is caused by a
deficiency of serotonin — a fable that by now has become as discredited
as the phlogiston theory of chemistry. It also stated that mental health
interventions are ‘evidence-based’ and ‘scientifically tested’ —
neglecting to mention that much of that evidence is put forth by drug
companies who have a fiduciary duty to do everything they can to
maximize sales of their products.”
“So is all this a scheme to push more drugs to more kids? The 2013/2014 annual report
for the National Council for Behavioral Health, titled ‘A Legacy of
Excellence and Impact,’ gives us a hint. It lists the organization’s
supporters as including the Pharmaceutical Research and Manufacturers of
America (PhRMA) along with no fewer than 12 different drug companies.
Would these folks be ponying up the cash if they weren’t confident this
program would increase sales? And do the parents and teachers who attend
the council’s training program — no doubt with the best intentions in
the world — realize that they are essentially sitting through an
eight-hour infomercial bought and paid for by the drugmakers?”
“One out of 13 American children between the ages of 6 and 17 has taken a psychotropic medication within the last six months, according to the Centers for Disease Control. Meanwhile, youth suicide rates are at their peak
going back at least as far back as 1999, while the number of children
receiving disability benefits for mental illness is at an all-time high.”
Continue Reading.
Thank You Dr Hickey
And bookmark Dr Hickey's URL.
Saturday, November 8, 2014
90% of Doctors Do Not Appropriately Monitor Children's Progress On ADHD Meds
madinamerica;
Thank You Mr Wipond and MIA.
see also:
State Med Boards Not Punishing Dangerous Docs
Medical Boards Lack Resources ??? To Punish Dangerous Docs
Are State Medical Boards Doing Enough To Protect Patients?
HHS: Doctor Malpractice, Disciplinary Data No Longer Public
State Rarely Investigates Hospital Complaints
November 8, 2014
Nearly one-third of pediatricians who treat children for ADHD do not follow the Diagnostic and Statistical Manual of Mental Disorders when diagnosing them, and 90% don’t do appropriate follow-up monitoring, according to research in Pediatrics. “A large number of pediatricians also do not gather parent and teacher ratings of a child’s day-to-day behavior, information that is crucial in diagnosing ADHD and tracking whether prescribed therapies are working,” reported Medical Xpress.
The research involved about 1,600 patient charts selected at random from 188 pediatric health care providers at 50 practices in central and northern Ohio.
Nine out of 10 children diagnosed with ADHD were taking psychiatric medication, while only one in 10 of those were receiving andjunct behavioral therapy or psychotherapy. Nearly half of the children taking medications had not even seen their treating pediatrician within the first month after being put on the drugs. And within the first year after prescribing ADHD medications, about 90% of physicians did not consult parents or teachers about the child’s progress.
“The quality of care seems to be very low and not in accord with American Academy of Pediatrics guidelines,” lead author Jeffery Epstein, director of the Center for ADHD, Behavioral Medicine and Clinical Psychology at Cincinnati Children’s Hospital, told Medical Xpress. Epstein called the findings “disturbing.”
Typical ADHD care leaves room for improvement, study finds (Medical Press, November 3, 2014)
(Abstract) Variability in ADHD Care in Community-Based Pediatrics (Epstein, Jeffery N. Pediatrics. Published online November 3, 2014. doi: 10.1542/peds.2014-1500)
Thank You Mr Wipond and MIA.
see also:
State Med Boards Not Punishing Dangerous Docs
Medical Boards Lack Resources ??? To Punish Dangerous Docs
Are State Medical Boards Doing Enough To Protect Patients?
HHS: Doctor Malpractice, Disciplinary Data No Longer Public
State Rarely Investigates Hospital Complaints
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